Methods, systems, and apparatus for closed-loop neuromodulation

ABSTRACT

Systems, apparatus, and methods for treating medication refractory epilepsy are disclosed. In one embodiment, a method of treating epilepsy is disclosed comprising detecting, using a first electrode array coupled to a first endovascular carrier, an electrophysiological signal of a subject. The method further comprises analyzing the electrophysiological signal using a neuromodulation unit electrically coupled to the first electrode array and stimulating an intracorporeal target of the subject using a second electrode array coupled to a second endovascular carrier implanted within a part of a bodily vessel superior to a base of the skull of the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Pat. Application No. 17/659,381filed on Apr. 15, 2022, which is a divisional of U.S. Pat. ApplicationNo. 17/398,854 filed on Aug. 10, 2021, which is a continuation ofInternational Patent Application No. PCT/US2020/059509 filed on Nov. 6,2020, which claims the benefit of U.S. Provisional Application No.62/932,906 filed on Nov. 8, 2019 and U.S. Provisional Application No.63/062,633 filed on Aug. 7, 2020, the contents of which are incorporatedherein by reference in their entireties.

TECHNICAL FIELD

This disclosure relates generally to endovascular neuromodulation and,more specifically, to methods, systems, and apparatus for closed-loopendovascular neuromodulation.

BACKGROUND

Vagal nerve stimulation has been successful at decreasing the frequencyof seizures for people with medically refractory epilepsy and those whomresection is not a suitable option. Over 100,000 people have beenimplanted with a vagal nerve stimulation (VNS) system, although theoutcome for such treatment is moderate. The responder rate, or the rateof patients who have their seizure frequencies reduced greater than 50%,is only 46.6%, with the median seizure reduction being 52.4%. Inaddition, there are potential side effects caused by the implantation ofcuff-like electrodes directly around the vagal nerve, including injuryand paralysis to the nerve and direct injury to the neck where surgicalincisions are required to expose the nerve for electrode implantation.

Current VNS stimulation parameters are oftentimes open-loop, meaningthat stimulation is administered continuously or according to a rigidschedule. Generally, stimulation is applied for around one to fiveminutes followed by a rest period for around four to ten minutes.Consequently, and due to the large amount of power being delivered,battery depletion is a concern as well as hardware malfunctions. Bothrequire additional surgery for the removal of any implantable units forreplacement of the battery or malfunctioning hardware components. Recentstudies have also drawn attention to several potential side effectsassociated with this type of continuous or constant stimulation. See,e.g., Sun FT, Morrell MJ, Wharen RE Jr., Responsive Cortical Stimulationfor the Treatment of Epilepsy. Neurotherapeutics, 2008 Jan 5(1): 68-74and Morrell M. Brain, Stimulation for Epilepsy: Can Scheduled orResponsive Neurostimulation Stop Seizures? Current Opinion in Neurology,2006 Apr; 19(2): 164-8.

Therefore, a solution is needed which addresses the above shortcomingsand disadvantages of traditional neuromodulation systems. Such asolution should be safe, effective, and not overly difficult to implant.

SUMMARY

Systems, apparatus, and methods for treating medication refractoryepilepsy are disclosed. In one embodiment, a method of treating epilepsycomprises detecting, using a first electrode array, anelectrophysiological signal of a subject. The first electrode array canbe coupled to a first endovascular carrier implanted within the subject.The method can also comprise analyzing the electrophysiological signalusing a neuromodulation unit implanted within the subject andelectrically coupled to the first electrode array and stimulating anintracorporeal target of the subject using a second electrode array inresponse to the electrophysiological signal detected. The secondelectrode array can be electrically coupled to the neuromodulation unit.The second electrode array can be coupled to a second endovascularcarrier implanted within part of a bodily vessel superior to a base of askull of the subject.

Stimulating the intracorporeal target can further comprise generating anelectrical impulse using a pulse generator electrically coupled to thesecond electrode array. The pulse generator can be implanted within thesubject. Generating the electrical impulse can further compriseincreasing a current amplitude of the electrical impulse from 0 mA to upto 10 mA in 0.1 mA steps and increasing a voltage of the electricalimpulse from 0 V to up to 10 V in 0.25 V steps. Moreover, the pulsewidth of the electrical impulse can be set at between 25 µS to about 600µS. Furthermore, the frequency of the electrical impulse can be set atbetween 1 Hz and 400 Hz.

In some embodiments, the method can also comprise delivering the firstendovascular carrier and the second endovascular carrier through asingular delivery catheter prior to detecting the electrophysiologicalsignal of the subject. In other embodiments, the method can comprisedelivering the first endovascular carrier through a first deliverycatheter and delivering the second endovascular carrier through a seconddelivery catheter prior to detecting the electrophysiological signal ofthe subject. In further embodiments, the method can comprise deliveringthe first endovascular carrier through a first delivery catheter anddelivering the second endovascular carrier through a second deliverycatheter extending through the first delivery catheter.

In some embodiments, the method can further comprise stimulating theintracorporeal target of the subject using the first electrode array. Inthese embodiments, the method can also comprise using the secondelectrode array to detect or record the electrophysiological signal ofthe subject.

Also disclosed is an endovascular neuromodulation system for treatingepilepsy and/or other conditions or disorders. The system can comprise afirst electrode array configured to detect an electrophysiologicalsignal of a subject. The first electrode array can be coupled to a firstendovascular carrier configured to be implanted within the subject. Thesystem can also comprise a second electrode array configured tostimulate an intracorporeal target of the subject. The second electrodearray can be coupled to a second endovascular carrier configured to beimplanted superior to a base of a skull of the subject. The system canfurther comprise an implantable neuromodulation unit electricallycoupled to the first electrode array and the second electrode array.

The neuromodulation unit can be configured to analyze theelectrophysiological signal detected by the first electrode array andgenerate an electrical impulse via a pulse generator to be transmittedto the second electrode array to stimulate the intracorporeal target inresponse to the electrophysiological signal detected.

The first endovascular carrier carrying the first electrode array can beimplanted or configured to be implanted within a venous sinus of thesubject. For example, the first endovascular carrier can be implanted orconfigured to be implanted within at least one of a superior sagittalsinus, an inferior sagittal sinus, a sigmoid sinus, a transverse sinus,and a straight sinus of the subject.

In some embodiments, the first endovascular carrier can be implanted orconfigured to be implanted within a superficial cerebral vein. Forexample, the first endovascular carrier can be implanted or configuredto be implanted within at least one of a vein of Labbe, a vein ofTrolard, a Sylvian vein, and a Rolandic vein.

In other embodiments, the first endovascular carrier can be implanted orconfigured to be implanted within a deep cerebral vein. For example, thefirst endovascular carrier can be implanted or configured to beimplanted within at least one of a vein of Rosenthal, a vein of Galen, asuperior thalamostriate vein, and an internal cerebral vein.

The first endovascular carrier can also be implanted within at least oneof a central sulcal vein, a post-central sulcal vein, and a pre-centralsulcal vein. In some embodiments, the first endovascular carrier canalso be implanted or configured to be implanted within a vesselextending through a hippocampus or amygdala of the subject.

The intracorporeal target can be part of a vagus nerve of the subject.The second endovascular carrier can be implanted or configured to beimplanted within part of an internal jugular vein superior to a jugularforamen of the subject. The second endovascular carrier can be implantedor configured to be implanted within a branch or tributary of theinternal jugular vein. The second endovascular carrier can also beimplanted within part of an internal carotid artery superior to the baseof the skull of the subject.

In some embodiments, the intracorporeal target can be a cerebellum ofthe subject. In these embodiments and other embodiments, the secondendovascular carrier can be implanted or configured to be implantedwithin at least one of a sigmoid sinus, a transverse sinus, and astraight sinus of the subject.

In other embodiments, the intracorporeal target can be a motor cortex ofthe subject. In these and other embodiments, the second endovascularcarrier can be implanted or configured to be implanted within at leastone of a superior sagittal sinus, an inferior sagittal sinus, a centralsulcal vein, a post-central sulcal vein, and a pre-central sulcal vein.

The second endovascular carrier can be implanted or configured to beimplanted within a superficial cerebral vein. For example, the secondendovascular carrier can be implanted or configured to be implantedwithin at least one of a vein of Labbe, a vein of Trolard, a Sylvianvein, and a Rolandic vein.

The second endovascular carrier can also be implanted or configured tobe implanted within a deep cerebral vein. For example, the secondendovascular carrier can be implanted or configured to be implantedwithin at least one of a vein of Rosenthal, a vein of Galen, a superiorthalamostriate vein, and an internal cerebral vein. In these and otherembodiments, the intracorporeal target can be at least one of ananterior nucleus of thalamus, a centromedian nucleus of thalamus, afornix, a hippocampus, a hypothalamus, a subthalamic nucleus, and acaudal zone incerta. In some embodiments, the second endovascularcarrier can also be implanted or configured to be implanted within avessel extending through a hippocampus or amygdala of the subject.

With respect to the implantation sites, the first endovascular carriercarrying the first electrode array and the second endovascular carriercarrying the second electrode array can be implanted in any combinationof the bodily vessels disclosed herein. For example, the firstendovascular carrier can be implanted within a venous sinus and thesecond endovascular carrier can be implanted within a superficialcerebral vein. Also, for example, the first endovascular carrier can beimplanted within a deep cerebral vein and the second endovascularcarrier can be implanted within an internal jugular vein.

The neuromodulation unit can be implanted or configured to be implantedwithin the subject. For example, the neuromodulation unit can beimplanted or configured to be implanted within a forearm of the subject.Alternatively, the neuromodulation unit can be implanted or configuredto be implanted within a pectoral region of the subject. Theneuromodulation unit can also be implanted or configured to be implantedwithin an armpit region of the subject.

The first electrode array can be electrically coupled to theneuromodulation unit via a first transmission lead having a first leaddiameter. The first transmission lead can extend through a neck of thesubject. The first lead diameter can be between about 0.5 mm and 1.5 mm.The second electrode array can be electrically coupled to theneuromodulation unit via a second transmission lead having a second leaddiameter. The second transmission lead can extend through a neck of thesubject. The second lead diameter can be between about 0.5 mm and 1.5mm. In other embodiments, the first electrode array and the secondelectrode array can be coupled to the neuromodulation unit via onetransmission lead having a lead diameter. The one transmission lead canextend through a neck of the subject. In these embodiments, the leaddiameter can be between about 0.5 mm and 1.5 mm.

In some embodiments, the pulse generator can be part of theneuromodulation unit. The pulse generator can be powered and activatedby an extracorporeal device. For example, the pulse generator cancomprise a first magnetic component and the extracorporeal device cancomprise a second magnetic component configured to be magneticallycoupled to the first magnetic component. The pulse generator can beconfigured to be charged by the extracorporeal device viaelectromagnetic induction when the extracorporeal device is placed inproximity to the pulse generator.

In these and other embodiments, the neuromodulation unit can be poweredby one or more batteries. The extracorporeal device can be provided aspart of an armband when the neuromodulation unit is implanted within anarm of the subject.

At least one of the first endovascular carrier and the secondendovascular carrier can be an expandable stent or endovascular scaffoldcomprising an electrode array coupled to the expandable stent orendovascular scaffold. For example, at least one of the firstendovascular carrier and the second endovascular carrier can be aself-expandable stent or self-expandable endovascular scaffold.

At least one of the first endovascular carrier and the secondendovascular carrier can be a wire or cable configured to be wound orcoiled comprising an electrode array coupled to the wire or cable. Thewire or cable can be wound in a substantially helical pattern. In someembodiments, at least one of the first endovascular carrier and thesecond endovascular carrier can be a wire or cable comprising a sharpdistal end for penetrating through lumen or vessel walls. Moreover, atleast one of the first endovascular carrier and the second endovascularcarrier can be a wire or cable comprising an anchor. For example, theanchor can be at least one of a barbed anchor and a radially-expandableanchor.

The neuromodulation unit can further comprise a telemetry unit. Thetelemetry unit can be configured to analyze the electrophysiologicalsignal detected by comparing the electrophysiological signal against oneor more signal thresholds or patterns. In some embodiments, theelectrophysiological signal can be a local field potential (LFP) and/oran intracranial/cortical EEG measured within a brain of the subject. Inthese and other embodiments, the electrophysiological signal can be anelectrocorticography signal.

The first endovascular carrier, the second endovascular carrier, and/orthe transmission lead can be made in part of platinum tungsten, gold,aluminum, Nitinol wire, rhodium, iridium, nickel, nickel-chromium alloy,gold-palladium-rhodium alloy, chromium-nickel-molybdenum alloy, and/orstainless steel.

Also disclosed is another method of treating epilepsy. The method cancomprise detecting, using a first electrode array, anelectrophysiological signal of a subject. The first electrode array canbe coupled to an endovascular carrier implanted superior to a base of askull of the subject. The method can further comprise analyzing theelectrophysiological signal using a neuromodulation unit electricallycoupled to the first electrode array. The method can also comprisestimulating an intracorporeal target of the subject using a secondelectrode array in response to the electrophysiological signal detected.The second electrode array can be coupled to the same endovascularcarrier.

Moreover, the electrodes of the second electrode array are separate fromthe electrodes of the first electrode array. In some embodiments, thefirst electrode array and the second electrode array can record ortransmit data to the neuromodulation unit via different channels.

Stimulating the intracorporeal target can further comprise generating anelectrical impulse using a pulse generator electrically coupled to thesecond electrode array. The pulse generator can be implanted within thesubject. Stimulating the intracorporeal target further can comprisegenerating an electrical impulse using a pulse generator electricallycoupled to the second electrode array. Generating the electrical impulsecan further comprise increasing a current amplitude of the electricalimpulse from 0 mA to up to 10 mA in 0.1 mA steps and increasing avoltage of the electrical impulse from 0 V to up to 10 V in 0.25 Vsteps. Moreover, the pulse width of the electrical impulse can be set atbetween 25 µS to about 600 µS. Furthermore, the frequency of theelectrical impulse can be set at between 1 Hz and 400 Hz.

Also disclosed is another endovascular neuromodulation system fortreating epilepsy and/or other conditions or disorders. The system cancomprise a first electrode array configured to detect anelectrophysiological signal of a subject. The first electrode array canbe coupled to an endovascular carrier configured to be implantedendovascularly superior to the base of the skull of the subject. Thesystem can also comprise a second electrode array configured tostimulate an intracorporeal target of the subject. The second electrodearray can be coupled to the same endovascular carrier. The system canfurther comprise an implantable neuromodulation unit electricallycoupled to the first electrode array and the second electrode array.

The neuromodulation unit can be configured to analyze theelectrophysiological signal detected by the first electrode array andgenerate an electrical impulse via a pulse generator to be transmittedto the second electrode array to stimulate the intracorporeal target inresponse to the electrophysiological signal detected.

The intracorporeal target can be part of a vagus nerve of the subject.The endovascular carrier can be implanted or configured to be implantedwithin part of an internal jugular vein superior to a jugular foramen ofthe subject. In some embodiments, the endovascular carrier can beimplanted or configured to be implanted within a branch or tributary ofthe internal jugular vein. The endovascular carrier can be implanted orconfigured to be implanted within part of an internal carotid arterysuperior to the base of the skull of the subject.

In some embodiments, the intracorporeal target can be a cerebellum ofthe subject. In these embodiments, the endovascular carrier can beimplanted or configured to be implanted within at least one of a sigmoidsinus, a transverse sinus, and a straight sinus of the subject.

In other embodiments, the intracorporeal target can be a motor cortex ofthe subject. In these embodiments, the endovascular carrier can beimplanted or configured to be implanted within at least one of asuperior sagittal sinus, an inferior sagittal sinus, a central sulcalvein, a post-central sulcal vein, and a pre-central sulcal vein.

The endovascular carrier can also be implanted within a superficialcerebral vein. For example, the endovascular carrier can be implanted orconfigured to be implanted within at least one of a vein of Labbe, avein of Trolard, a Sylvian vein, and a Rolandic vein.

The endovascular carrier can be implanted or configured to be implantedwithin a deep cerebral vein. For example, the endovascular carrier canbe implanted or configured to be implanted within at least one of a veinof Rosenthal, a vein of Galen, a superior thalamostriate vein, and aninternal cerebral vein.

The neuromodulation unit can be implanted or configured to be implantedwithin the subject. For example, the neuromodulation unit can beimplanted or configured to be implanted within a forearm of the subject.Alternatively, the neuromodulation unit can be implanted or configuredto be implanted within a pectoral region of the subject. Theneuromodulation unit can also be implanted or configured to be implantedwithin an armpit region of the subject.

The first electrode array can be electrically coupled to theneuromodulation unit via a first transmission lead having a first leaddiameter. The first transmission lead can extend through a neck of thesubject. The first lead diameter can be between about 0.5 mm and 1.5 mm.The second electrode array can be electrically coupled to theneuromodulation unit via a second transmission lead having a second leaddiameter. The second transmission lead can extend through a neck of thesubject. The second lead diameter can be between about 0.5 mm and 1.5mm.

In other embodiments, the first electrode array and the second electrodearray can be coupled to the neuromodulation unit via one transmissionlead having a lead diameter. The one transmission lead can extendthrough a neck of the subject. In these embodiments, the lead diametercan be between about 0.5 mm and 1.5 mm.

In some embodiments, the pulse generator can be part of theneuromodulation unit. The pulse generator can be powered and activatedby an extracorporeal device. For example, the pulse generator cancomprise a first magnetic component and the extracorporeal device cancomprise a second magnetic component configured to be magneticallycoupled to the first magnetic component. The pulse generator can beconfigured to be charged by the extracorporeal device viaelectromagnetic induction when the extracorporeal device is placed inproximity to the pulse generator.

In these and other embodiments, the neuromodulation unit can be poweredby one or more batteries. The extracorporeal device can be provided aspart of an armband when the neuromodulation unit is implanted within anarm of the subject.

In some embodiments, the endovascular carrier can be an expandable stentor endovascular scaffold comprising an electrode array coupled to theexpandable stent or endovascular scaffold. For example, the endovascularcarrier can be a self-expandable stent or self-expandable endovascularscaffold.

In other embodiments, the endovascular carrier can be a wire or cableconfigured to be wound or coiled comprising an electrode array coupledto the wire or cable. The wire or cable can be wound in a substantiallyhelical pattern.

In some embodiments, the endovascular carrier can be a wire or cablecomprising a sharp distal end for penetrating through lumen or vesselwalls. Moreover, the endovascular carrier can be a wire or cablecomprising an anchor. For example, the anchor can be at least one of abarbed anchor and a radially-expandable anchor.

The neuromodulation unit can further comprise a telemetry unit. Thetelemetry unit can be configured to analyze the electrophysiologicalsignal detected by comparing the electrophysiological signal against oneor more signal thresholds or patterns. In some embodiments, theelectrophysiological signal can be a local field potential (LFP) and/oran intracranial/cortical EEG measured within a brain of the subject. Inthese and other embodiments, the electrophysiological signal can be anelectrocorticography signal.

The endovascular carrier and/or the transmission lead(s) can be made inpart of platinum tungsten, gold, aluminum, Nitinol wire, rhodium,iridium, nickel, nickel-chromium alloy, gold-palladium-rhodium alloy,chromium-nickel-molybdenum alloy, and/or stainless steel.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings shown and described are exemplary embodiments andnon-limiting. Like reference numerals indicate identical or functionallyequivalent features throughout.

FIG. 1 illustrates one embodiment of an endovascular neuromodulationsystem for treating epilepsy and other disorders/conditions.

FIGS. 2A-2D illustrate various embodiments of endovascular carriers.

FIG. 3A illustrates possible implantation sites for components of theneuromodulation system.

FIG. 3B illustrates a neuromodulation unit implanted within an arm of asubject.

FIGS. 4A-4C illustrate one embodiment of a transmission lead used toconnect an electrode array to another electrode array or to theneuromodulation unit.

FIGS. 5A-5C illustrate an example method of implanting an embodiment ofan electrode array.

FIG. 6 illustrates one embodiment of a method of treating epilepsy.

FIG. 7 illustrates another embodiment of a method of treating epilepsy.

FIG. 8A illustrates an embodiment of an endovascular carrier implantedwithin an internal jugular vein of a subject.

FIG. 8B illustrates a partial sectional view of a transverse section ofa subject at the level of the C6 vertebra showing the vagus nerve andsurrounding vessels.

FIG. 8C illustrates a proximity of the internal jugular vein to thevagus nerve.

FIGS. 9A-9G illustrate certain veins and sinuses that can serve asimplantation sites for the endovascular carriers.

FIG. 10 illustrates one embodiment of a method of deploying ordelivering endovascular carriers.

FIG. 11 illustrates another embodiment of a method of deploying ordelivering the endovascular carriers.

FIG. 12 illustrates yet another embodiment of a method of deploying ordelivering the endovascular carriers.

FIG. 13 illustrates an embodiment of a delivery catheter comprising abifurcated transmission lead.

DETAILED DESCRIPTION

FIG. 1 illustrates one embodiment of an endovascular neuromodulationsystem 100 for treating epilepsy and other disorders/conditions. Theneuromodulation system 100 can comprise a plurality of electrode arrays102 electrically coupled to a neuromodulation unit 104 via transmissionleads 106 or wires. For example, the neuromodulation system 100 cancomprise a first electrode array 102A and a second electrode array 102Belectrically coupled to the neuromodulation unit 104.

Each of the electrode arrays 102 can be coupled to an endovascularcarrier 108. For example, the first electrode array 102A can be coupledto a first endovascular carrier 108A configured to be implantedendovascularly within the subject. The second electrode array 102B canbe coupled to a second endovascular carrier 108B configured to beimplanted endovascularly within the subject.

In some embodiments, the first endovascular carrier 108A and the secondendovascular carrier 108B can be implanted within different vessels(e.g., different veins, arteries, or sinuses) of the subject. In otherembodiments, the first endovascular carrier 108A and the secondendovascular carrier 108B can be implanted within the same vessel orwithin different segments of the same vessel.

In certain embodiments, the first electrode array 102A can be configuredto detect or record an electrophysiological signal of a subject and thesecond electrode array 102B can be configured to stimulate anintracorporeal target (e.g., a target nerve, a target brain region orarea, or other target tissue) of the subject. In these embodiments, theneuromodulation unit 104 can be configured to analyze theelectrophysiological signal detected or recorded by the first electrodearray 102A and transmit an electrical impulse to the second electrodearray 102B via a pulse generator 110 in response to theelectrophysiological signal detected or recorded.

In other embodiments, the first electrode array 102A and the secondelectrode array 102B can both be configured to detect or record anelectrophysiological signal of the subject. In additional embodiments,the first electrode array 102A and the second electrode array 102B canboth be configured to stimulate one or more intracorporeal targets ofthe subject. The intracorporeal target(s) will be discussed in moredetail in later sections.

The first electrode array 102A can comprise a plurality of electrodes112 coupled to the first endovascular carrier 108A. For example, thefirst electrode array 102A can comprise between 2 and 16 electrodes. Inother embodiments, the first electrode array 102A can comprise between16 and 20 electrodes or more than 20 electrodes.

The second electrode array 102B can comprise a plurality of electrodes112 coupled to the second endovascular carrier 108B. For example, thesecond electrode array 102B can comprise between 2 and 16 electrodes. Inother embodiments, the second electrode array 102B can comprise between16 and 20 electrodes or more than 20 electrodes.

When the electrode arrays 102 (e.g., any of the first electrode array102A or the second electrode array 102B) are used to detect or record anelectrophysiological signal of the subject, the electrode arrays can bereferred to as recording electrode arrays. Moreover, when the electrodearrays (e.g., any of the first electrode array 102A or the secondelectrode array 102B) are used to stimulate an intracorporeal target ofthe subject, the electrode arrays can be referred to as stimulatingelectrode arrays.

In some embodiments (for example, the embodiment shown in FIG. 1 ), thefirst endovascular carrier 108A and the second endovascular carrier 108Bcan be expandable stents or endovascular scaffolds. The endovascularcarrier and the electrode arrays coupled to such a carrier can bereferred to as a stent-electrode array 109. Stent-electrode arrays 109will be discussed in more detail in later sections.

In other embodiments, at least one of the first endovascular carrier108A and the second endovascular carrier 108B can be a biocompatiblecoiled wire 200 (see, e.g., FIG. 2A), a biocompatible anchored wire 208(see, e.g., FIG. 2C), or a combination thereof.

In certain embodiments, the first endovascular carrier 108A can be thesame as the second endovascular carrier 108B (e.g., both the firstendovascular carrier 108A and the second endovascular carrier 108B canbe stent-electrode arrays 109, coiled wires 200, or anchored wires 208).In other embodiments, the first endovascular carrier 108A can bedifferent from the second endovascular carrier 108B (e.g., the firstendovascular carrier 108A can be a stent-electrode array 109 and thesecond endovascular carrier 108B can be a coiled wire 200).

Although FIG. 1 illustrates the neuromodulation system 100 comprisingtwo electrode arrays 102 and two endovascular carriers 108, it iscontemplated by this disclosure that the neuromodulation system 100 cancomprise between three to five electrode arrays 102 and endovascularcarriers 108. In additional embodiments, the neuromodulation system 100can comprise between five to ten electrode arrays 102 and endovascularcarriers 108.

The neuromodulation unit 104 can be configured to be implanted withinthe subject. In some embodiments, the neuromodulation unit 104 can beconfigured to be implanted within a forearm of the subject (see, e.g.,FIG. 3B). In other embodiments, the neuromodulation unit 104 can beconfigured to be implanted within a pectoral region of the subject (see,e.g., FIG. 3A). The neuromodulation unit 104 can also be implanted orconfigured to be implanted within an armpit region of the subject.

Each of the first electrode array 102A and the second electrode array102B can be coupled via one or more transmission leads 106 or lead wiresto the neuromodulation unit 104. In some embodiments, the transmissionleads 106 can be inserted or otherwise coupled to a header portion 114of the neuromodulation unit 104.

The header portion 114 can comprise a different plug receptor for leadsor plugs coming from different electrode arrays. For example, the headerportion 114 can comprise a 0.9 mm plug receptor for receiving a plug orconnector from a first transmission lead 106A connected or coupled tothe first electrode array 102A serving as the recording electrode arrayand a 1.3 mm plug receptor for receiving a plug or connector from asecond transmission lead 106B connected or coupled to the secondelectrode array 102B serving as the stimulation electrode array.

The neuromodulation unit 104 can comprise a unit housing 116. The unithousing 116 can be a hermetically sealed housing or casing such thatelectronic components within the neuromodulation unit 104 areencapsulated by the unit housing 116. The unit housing 116 can be madeof a biocompatible material. For example, the unit housing 116 can bemade in part of a metallic material (e.g., titanium, stainless steel,platinum, or a combination thereof), a polymeric material, or acombination thereof.

In some embodiments, the pulse generator 110 can be part of theneuromodulation unit 104 or contained within the unit housing 116. Insome embodiments, the implantable neuromodulation unit 104 can compriseone or more batteries (e.g., rechargeable or non-rechargeablebatteries). In certain embodiments, the batteries of the neuromodulationunit 104 can be recharged via wireless inductive charging.

In other embodiments, the neuromodulation unit 104 can be powered and/oractivated by an extracorporeal device 300 (see, for example, FIG. 3A).The neuromodulation unit 104 can comprise a first magnetic component 118and the extracorporeal device 300 can comprise a second magneticcomponent 302 (see, for example, FIG. 3A) configured to be magneticallycoupled to the first magnetic component 118. The neuromodulation unit104, including the pulse generator 110, can be configured to be chargedby the extracorporeal device 300 via electromagnetic induction oractivated by the extracorporeal device 300 when the extracorporealdevice 300 is placed in proximity to the neuromodulation unit 104, suchas by holding the extracorporeal device 300 close to an implantationsite of the neuromodulation unit 104. In these embodiments where theneuromodulation unit 104 and the pulse generator 110 are the samedevice, any reference to the neuromodulation unit 104 can also refer tothe pulse generator 110.

In other embodiments, the pulse generator 110 can be a separate deviceor apparatus from the neuromodulation unit 104. In these embodiments,the pulse generator 110 can be implanted within the subject and theneuromodulation unit 104 can be an extracorporeal unit located andoperating outside of the body of the subject. In these embodiments, theneuromodulation unit 104 can serve as the extracorporeal device 300 andcan process data received wirelessly or via physical leads from thefirst electrode array 102A, the second electrode array 102B, or acombination thereof.

In further embodiments, the implantable pulse generator 110 can compriseone or more batteries (e.g., rechargeable or non-rechargeablebatteries). In certain embodiments, the batteries of the pulse generator110 can be recharged via wireless inductive charging.

When the pulse generator 110 is a separate device implanted within thesubject (e.g., implanted within the forearm, the pectoral region, thearmpit region, etc.), the pulse generator 110 can be powered andactivated by the extracorporeal device 300 (see, e.g., FIG. 3A). In someembodiments, the pulse generator 110 can comprise a first magneticcomponent 118 and the extracorporeal device 300 can comprise a secondmagnetic component 302 configured to be magnetically coupled to thefirst magnetic component 118. The pulse generator 110 can be configuredto be charged by the extracorporeal device 300 via electromagneticinduction when the extracorporeal device 300 is placed in proximity tothe pulse generator 110, such as by holding the extracorporeal device300 close to an implantation site of the pulse generator 110.

The neuromodulation unit 104 can further comprise a telemetry unit 120or telemetry module (e.g., a telemetry hardware module, a telemetrysoftware module, or a combination thereof). The telemetry unit 120 canbe configured to analyze the electrophysiological signal detected orrecorded by an electrode array by comparing the electrophysiologicalsignal against one or more predetermined signal thresholds or patterns.For example, the neuromodulation unit 104 (or the telemetry unit 120within the neuromodulation unit 104) can comprise one or more processorsand one or more memory units. The one or more processors can beprogrammed to execute instructions stored in the one or more memoryunits to compare the electrophysiological signal against one or morepredetermined signal thresholds or patterns as part of the analysis.

In some embodiments, the electrophysiological signal can be a localfield potential (LFP) and/or an intracranial/cortical EEG measuredwithin a brain of the subject using any of the electrode arrays (e.g.,the first electrode array 102A, the second electrode array 102B, or acombination thereof) implanted endovascularly within the subject. Inother embodiments, the electrophysiological signal can be anintracranial or cortical electroencephalography (EEG) signal.

In other embodiments, the electrophysiological signal can be anelectrocorticography (ECoG) signal received by the telemetry unit 120from an ECoG electrode array deployed on a surface of the brain. Forexample, the ECoG electrode array can be a flexible or stretchableelectrode-mesh or one or more electrode patches placed on a surface ofthe brain.

In further embodiments, the electrophysiological signal can be a signalindicating a heart rate or change in heart rate of the subject. Forexample, the electrophysiological signal can be an electrocardiogram(ECG/EKG) signal measured by the neuromodulation unit 104 when theneuromodulation unit 104 is implanted within a pectoral region orimplanted within a subclavian space of the subject.

In certain embodiments, the electrophysiological signal can be an EEGsignal received by the telemetry unit 120 from a plurality of externalelectrodes (an external electrode array) placed on a scalp of thesubject. For example, the EEG signal can be obtained from a head-mountedEEG monitoring system (e.g., EEG skull cap or EEG-visor). In theseembodiments, the EEG electrodes can serve as the recording or detectingelectrode array.

The electrophysiological signal can provide information or data that canbe used to predict or indicate whether the subject is about toexperience an epileptic seizure. For example, when theelectrophysiological signal is an EEG signal, the neuromodulation unit104 can command the pulse generator 110 to generate an electricalimpulse when epileptiform transients or other seizure pre-onsetsignatures are detected in the EEG signal.

The neuromodulation unit 104 (or the telemetry unit 120) can adjust orvary one or more signal thresholds. Moreover, the neuromodulation unit104 can also select from different signal thresholds. For example, theneuromodulation unit 104 can raise or lower a signal threshold based onhow often the subject experiences a seizure after a signal threshold ismet (or not met).

The neuromodulation system 100 can be considered to operate in aclosed-loop mode or to provide “responsive neurostimulation” when theintracorporeal target is stimulated in response to a detectedelectrophysiological signal associated or correlated with the onset ofepileptic seizures. In some embodiments, the system 100 can alsoclassify or stratify the electrophysiological signals detected orrecorded into low risk, medium risk, or high risk and only generate theelectrical impulse when the signal is considered medium risk or highrisk.

The neuromodulation unit 104 can be configured to analyze theelectrophysiological signal detected or recorded by at least one of theelectrode arrays (e.g., any of the first electrode array 102A, thesecond electrode array 102B, or a combination thereof) and transmit anelectrical impulse to the same electrode array or another electrodearray via the pulse generator 110 in response to theelectrophysiological signal detected or recorded.

The electrical impulse can be biphasic, monophasic, sinusoidal, or acombination thereof. The pulse generator 110 can generate the electricalimpulse by increasing a current amplitude of the electrical impulse from0 mA to up to 10 mA in 0.1 mA steps and increasing a voltage of theelectrical impulse from 0 V to up to 10 V in 0.25 V steps. Theelectrical impulse generated can have a pulse width of between 25 µS toabout 600 µS. A timing parameter of the electrical impulse can also beadjusted to allow for different stimulation timing patterns.

The electrical impulse generated can have a frequency between 1 Hz and400 Hz. For example, a frequency of the electrical impulse can be set ata low frequency (between about 1 Hz to 10 Hz), a medium frequency(between about 10 Hz to 150 Hz), and a high frequency (between about 150Hz to 400 Hz). Stimulating the intracorporeal target (e.g., the vagusnerve) can increase blood flow to key areas of the brain and raiselevels of certain neurotransmitters involved in suppressing seizureactivity (e.g., inhibitory neurotransmitters such as gamma-aminobutyricacid (GABA)).

In other embodiments, the neuromodulation system 100 can operate in anopen-loop mode or configuration such that the intracorporeal target isstimulated via an electrode array intermittently or periodically basedon a pre-set schedule.

FIGS. 2A-2D illustrates various other embodiments of endovascularcarriers 108 that can be used to carry an electrode array 102 and securethe electrode array 102 to an implantation site within a vasculature ofthe subject.

As previously shown in FIG. 1 , the endovascular carrier 108 can be anexpandable stent or endovascular scaffold comprising an electrode array102 coupled to the expandable stent or endovascular scaffold. Theexpandable stent or endovascular scaffold can comprise multiplefilaments woven into a tubular-like structure.

In some embodiments, the stent or scaffold is configured to beself-expandable. For example, the stent or scaffold can self-expand froma collapsed or crimped configuration to an expanded configuration whendeployed within a vasculature of the subject. For example, the stent orscaffold can self-expand into a shape or diameter pre-set to fit aparticular vein, artery, or another vessel. In other embodiments, thestent or scaffold can be expanded by a balloon catheter.

The electrodes 112 of the electrode array 102 can be affixed, secured,or otherwise coupled to an external boundary or radially outward portionof the expandable stent or scaffold. For example, the electrodes 112 ofthe electrode array 102 can be arranged along filaments making up theexternal boundary or radially outward portion of the expandable stent orscaffold (i.e., the part of the stent or scaffold configured to be incontact with the vessel lumen).

In some embodiments, the filaments of the expandable stent orendovascular scaffold can be made in part of a shape-memory alloy. Forexample, the filaments of the expandable stent or endovascular scaffoldcan be made in part of Nitinol (e.g., Nitinol wire). The filaments ofthe expandable stent or endovascular scaffold can also be made in partof stainless steel, gold, platinum, nickel, titanium, tungsten,aluminum, nickel-chromium alloy, gold-palladium-rhodium alloy,chromium-nickel-molybdenum alloy, iridium, rhodium, or a combinationthereof. The filaments of the expandable stent or endovascular scaffoldcan also be made in part of a shape memory polymer.

When the endovascular carrier 108 is an expandable stent or endovascularscaffold carrying an electrode array 102, the entire carrier and arrayassembly can be referred to as a stent-electrode array 109.

The stent-electrode arrays 109 disclosed herein can be any of thestents, scaffolds, stent-electrodes, or stent-electrode arrays disclosedin U.S. Pat. Pub. No. US 2020/0363869; U.S. Pat. Pub. No. 2020/0078195;U.S. Pat. Pub. No. 2020/0016396; U.S. Pat. Pub. No. 2019/0336748; U.S.Pat. Pub. No. US 2014/0288667; U.S. Pat. No. 10,575,783; U.S. Pat. No.10,485,968; U.S. Pat. No. 10,729,530, U.S. Pat. No. 10,512,555; U.S.Pat. App. No. 62/927,574 filed on Oct. 29, 2019; U.S. Pat. App. No.62/932,906 filed on Nov. 8, 2019; U.S. Pat. App. No. 62/932,935 filed onNov. 8, 2019; U.S. Pat. App. No. 62/935,901 filed on Nov. 15, 2019; U.S.Pat. App. No. 62/941,317 filed on Nov. 27, 2019; U.S. Pat. App. No.62/950,629 filed on Dec. 19, 2019; U.S. Pat. App. No. 63/003,480 filedon Apr. 1, 2020; U.S. Pat. App. No. 63/057,379 filed on Jul. 28, 2020,the contents of which are incorporated herein by reference in theirentireties.

FIG. 2A illustrates another embodiment of the endovascular carrier 108as a coiled wire 200. The coiled wire 200 can be used in vessels thatare too small to accommodate the stent-electrode array 109.

The coiled wire 200 can be a biocompatible wire 202 or microwireconfigured to wind itself into a coiled pattern or a substantiallyhelical pattern. The electrodes 112 of the electrode array 102 can bearranged such that the electrodes 112 are scattered along a length ofthe coiled wire 200. More specifically, the electrodes 112 of theelectrode array 102 can be affixed, secured, or otherwise coupled todistinct points along a length of the coiled wire 200. The electrodes112 of the electrode array 102 can be separated from one another suchthat no two electrodes 112 are within a predetermined separationdistance (e.g., at least 10 µm, at least 100 µm, or at least 1.0 mm)from one another.

In some embodiments, the wire 202 or microwire can be configured toautomatically wind itself into a coiled configuration (e.g., helicalpattern) when the wire 202 or microwire is deployed out of a deliverycatheter. For example, the coiled wire 200 can automatically attain itscoiled configuration via shape memory when the delivery catheter orsheath is retracted. The coiled configuration or shape can be a presetor shape memory shape of the wire 202 or microwire prior to the wire 202or microwire being introduced into a delivery catheter. The preset orpre-trained shape can be made to be larger than the diameter of theanticipated deployment or implantation vessel to enable the radial forceexerted by the coils to secure or position the coiled wire 200 in placewithin the deployment or implantation vessel.

In other embodiments, the coiled wire 200 can attain the coiledconfiguration when a pushing force is applied to the wire 202 ormicrowire to compel or otherwise bias the wire 202 or microwire into thecoiled configuration.

As shown in FIG. 2A, the coiled wire 200 can have a wire diameter 204and a coil diameter 206. The wire diameter 204 can be a diameter of theunderlying wire 202 or microwire used to form the endovascular carrier108. In some embodiments, the wire diameter 204 can be between about 25µm to about 1.0 mm. In other embodiments, the wire diameter 204 can bebetween about 100 µm to about 500 µm.

The coil diameter 206 can be between 1.0 mm to 15.0 mm. Morespecifically, the coil diameter 206 can be between about 3.0 mm to about8.0 mm (e.g., about 6.0 mm or 7.0 mm). In some embodiments, the coildiameter 206 can be between 15.0 mm to about 25.0 mm. The coil diameter206 can be set based on a diameter of a target vessel or deploymentvessel.

The wire 202 or microwire can be made in part of a shape-memory alloy, ashape memory polymer, or a combination thereof. For example, wire 202 ormicrowire can be made in part of Nitinol (e.g., Nitinol wire). The wire202 or microwire can also be made in part of stainless steel, gold,platinum, nickel, titanium, tungsten, aluminum, nickel-chromium alloy,gold-palladium-rhodium alloy, chromium-nickel-molybdenum alloy, iridium,rhodium, or a combination thereof.

FIG. 2B illustrates that a first electrode array 102A can be carried bya first coiled wire 200A and a second electrode array 102B can becarried by a second coiled wire 200B connected to the first coiled wire200A. In this embodiment, the first coiled wire 200A can serve as thefirst endovascular carrier 108A and the second coiled wire 200B canserve as the second endovascular carrier 108B. Each of the first coiledwire 200A and the second coiled wire 200B can be the same as the coiledwire 200 (see FIG. 2A) previously discussed.

The first coiled wire 200A can be connected to the second coiled wire200B by an uncoiled segment of the wire 202 or microwire. For example,the first coiled wire 200A can be connected to the second coiled wire200B by an uncoiled segment of the same wire 202 or microwire used tomake the first coiled wire 200A and the second coiled wire 200B.

As will be discussed in more detail in later sections, the first coiledwire 200A serving as the first endovascular carrier 108A and the secondcoiled wire 200B serving as the second endovascular carrier 108B can beimplanted along different segments of the same vessel or implantedwithin different vessels.

In some embodiments, the first electrode array 102A carried by the firstcoiled wire 200A can serve as a recording electrode array and the secondelectrode array 102B carried by the second coiled wire 200B can serve asthe stimulating electrode array. In other embodiments, both the firstelectrode array 102A carried by the first coiled wire 200A and thesecond electrode array 102B carried by the second coiled wire 200B canserve as the recording electrode arrays and/or the stimulating electrodearrays.

FIG. 2C illustrates a further embodiment of the endovascular carrier 108as an anchored wire 208. The anchored wire 208 can be used in vesselsthat are too small or too tortuous to accommodate either the coiled wire200 or the stent-electrode array 109.

The anchored wire 208 can comprise a biocompatible wire 202 or microwireattached or otherwise coupled to an anchor or another type ofendovascular securement mechanism.

FIG. 2C illustrates that the anchored wire 208 can comprise a barbedanchor 210, a radially-expandable anchor 212, or a combination thereof(both the barbed anchor 210 and the radially-expandable anchor 212 areshown in broken or phantom lines in FIG. 2C).

In some embodiments, the barbed anchor 210 can be positioned at a distalend of the anchored wire 208. In other embodiments, the barbed anchor210 can be positioned along one or more sides of the wire 202 ormicrowire. The barbs of the barbed anchor 210 can secure or moor theanchored wire 208 to an implantation site within the subject.

The radially-expandable anchor 212 can be a segment of the wire 202 ormicrowire shaped as a coil or loop. The coil or loop can be sized toallow the coil or loop to conform to a vessel lumen and to expandagainst a lumen wall to secure the anchored wire 208 to an implantationsite within the vessel. For example, the coil or loop can be sized to belarger than the diameter of the anticipated deployment or implantationvessel to enable the radial force exerted by the coil or loop to secureor position the anchored wire 208 in place within the deployment orimplantation vessel.

In some embodiments, the radially-expandable anchor 212 can bepositioned at a distal end of the anchored wire 208. In otherembodiments, the radially-expandable anchor 212 can be positioned alonga segment of the anchored wire 208 proximal to the distal end.

The electrodes 112 of the electrode array 102 can be scattered along alength of the coiled wire 200. More specifically, the electrodes 112 ofthe electrode array 102 can be affixed, secured, or otherwise coupled todistinct points along a length of the anchored wire 208. The electrodes112 of the electrode array 102 can be separated from one another suchthat no two electrodes 112 are within a predetermined separationdistance (e.g., at least 10 µm, at least 100 µm, or at least 1.0 mm)from one another.

Although FIG. 2C illustrates the anchored wire 208 having only onebarbed anchor 210 and one radially-expandable anchor 212, it iscontemplated by this disclosure that the anchored wire 208 can comprisea plurality of barbed anchors 210 and/or radially-expandable anchors212.

FIG. 2D illustrates an embodiment of an endovascular carrier 214carrying different electrode arrays 102 (e.g., the first electrode array102A and the second electrode array 102B). As shown in FIG. 2D, theendovascular carrier 214 can be the stent-electrode array 109 previouslydiscussed.

In this embodiment, two electrode arrays 102 can be coupled to the sameexpandable stent or endovascular scaffold. In other embodiments, threeor more electrode arrays 102 can be coupled to the same expandable stentor endovascular scaffold.

Although FIG. 2D illustrates the electrodes 112 of the first electrodearray 102A using dark circles and the electrodes 112 of the secondelectrode array 102B using white circles, it should be understood by oneof ordinary skill in the art that the difference in color is only forease of illustration.

The electrodes 112 of the first electrode array 102A can be used asdedicated recording or detection electrodes and the electrodes 112 ofthe second electrode array 102B can be used as dedicated stimulatingelectrodes. In this manner, only one endovascular carrier is needed todeploy both the recording electrode array and the stimulating electrodearray. Moreover, in this embodiment, the electrodes 112 of the firstelectrode array 102A can record and communicate via different data orcommunication channels than electrodes 112 of the second electrode array102B.

Although FIG. 2D illustrates the endovascular carrier 214 as anexpandable stent or scaffold, it is contemplated by this disclosure thatany of endovascular carriers disclosed herein, including the coiled wire200 and the anchored wire 208, can be used as an endovascular carrierfor carrying the at least two types of electrode arrays 102.

The electrodes 112 of the electrode arrays 102 depicted in FIGS. 2A-2Dcan be made in part of platinum, platinum black, another noble metal, oralloys or composites thereof. For example, the electrodes 112 of theelectrode arrays 102 can be made of gold, iridium, palladium, agold-palladium-rhodium alloy, rhodium, or a combination thereof. In someembodiments, the electrodes 112 can be made of a metallic composite witha high charge injection capacity (e.g., a platinum-iridium alloy orcomposite).

In some embodiments, the electrodes 112 can be shaped as circular diskshaving a disk diameter of between about 100 µm to 1.0 mm. In otherembodiments, the electrodes 112 can have a disk diameter of between 1.0mm and 1.5 mm. In additional embodiments, the electrodes 112 can becylindrical, spherical, cuff-shaped, ring-shaped, partially ring-shaped(e.g., C-shaped), or semi-cylindrical,

The electrodes 112 can have their conductive properties enhanced byincreasing the surface area of the electrodes 112 through surfaceroughening with chemical or electrochemical roughening methods orcoating with a conductive polymeric coating such aspoly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS).

FIG. 3A illustrates that the neuromodulation unit 104 and theendovascular carriers 108 carrying the electrode arrays 102 can beimplanted within the subject. In some embodiments, the neuromodulationunit 104 can be powered by a portable power supply such as one or morerechargeable batteries. In these and other embodiments, the batteries ofthe neuromodulation unit 104 can be recharged by an extracorporealdevice 300 via electromagnetic induction. In some embodiments, theneuromodulation unit 104 can also be activated or powered by theextracorporeal device 300 when the extracorporeal device 300 is placedin proximity to the neuromodulation unit 104 (e.g., when held up next tothe implantation site of the neuromodulation unit 104).

For example, the neuromodulation unit 104 can comprise a first magneticcomponent 118 (e.g., a receiving or secondary coil) and theextracorporeal device 300 can comprise a second magnetic component 302(e.g., a primary or transmission coil) configured to be magneticallycoupled to the first magnetic component 118. The extracorporeal device300 can charge or power the neuromodulation unit 104 via electromagneticinduction.

In some embodiments, the pulse generator 110 can be a standalone deviceseparate from the neuromodulation unit 104. In these embodiments, thepulse generator 110 can also comprise a first magnetic component 118(e.g., a receiving or secondary coil) configured to be magneticallycoupled to a second magnetic component 302 (e.g., a primary ortransmission coil) within the extracorporeal device 300. In theseembodiments, the pulse generator 110 can be charged or powered by theextracorporeal device 300 via electromagnetic induction.

As shown in FIG. 3A, any of the endovascular carriers 108 can beimplanted within a cortical or cerebral vessel of the subject. Forexample, an electrode array 102 coupled to a stent-electrode array 109serving as the endovascular carrier 108 can be implanted within a venoussinus (e.g., a superior sagittal sinus) of the subject. Thestent-electrode array 109 can be connected or coupled directly to theneuromodulation unit 104 via its own transmission lead 106 or cable. Inother embodiments, the stent-electrode array 109 can be coupled to theneuromodulation unit 104 via a shared transmission lead 106 or cable.

In some embodiments, the stent-electrode array 109 deployed within thevenous sinus can be used to detect or record an electrophysiologicalsignal of the subject (i.e., used as a recording electrode array). Inother embodiments, the stent-electrode array 109 deployed within thevenous sinus can be used to stimulate an intracorporeal target (e.g., amotor cortex) of the subject. In this manner, the stent-electrode array109 deployed within the venous sinus can be used as a stimulatingelectrode array. In further embodiments, the stent-electrode array 109deployed within the venous sinus can be used as both a recordingelectrode array and a stimulating electrode array (see, e.g., thestent-electrode array of FIG. 2D).

FIG. 3A also illustrates that an electrode array 102 coupled to a coiledwire 200 serving as the endovascular carrier 108 can be implanted withina superficial cerebral vein (e.g., a vein of Trolard) of the subject.The coiled wire 200 can be connected or coupled directly to theneuromodulation unit 104 via its own transmission lead 106 or cable. Inother embodiments, the coiled wire 200 can be coupled to theneuromodulation unit 104 via a shared transmission lead 106 or cable.

In some embodiments, the coiled wire 200 deployed within the superficialcerebral vein can be used to detect or record an electrophysiologicalsignal of the subject (i.e., used as a recording electrode array). Inother embodiments, the coiled wire 200 deployed within the superficialcerebral vein can be used to stimulate an intracorporeal target (e.g., amotor cortex) of the subject. In this manner, the coiled wire 200deployed within the superficial cerebral vein can be used as astimulating electrode array. In further embodiments, the coiled wire 200deployed within the superficial cerebral vein can be used as both arecording electrode array and a stimulating electrode array.

FIG. 3A further illustrates that an electrode array 102 coupled to ananchored wire 208 serving as the endovascular carrier 108 can beimplanted within a deep cerebral vein (e.g., a superior thalamostriatevein) of the subject. The anchored wire 208 can be connected or coupleddirectly to the neuromodulation unit 104 via its own transmission lead106 or cable. In other embodiments, the anchored wire 208 can be coupledto the neuromodulation unit 104 via a shared transmission lead 106 orcable.

In some embodiments, the anchored wire 208 deployed within the deepcerebral vein can be used to detect or record an electrophysiologicalsignal of the subject (i.e., used as a recording electrode array). Inother embodiments, the anchored wire 208 deployed within the deepcerebral vein can be used to stimulate an intracorporeal target (e.g.,an anterior nucleus of thalamus) of the subject. In this manner, theanchored wire 208 deployed within the deep cerebral vein can be used asa stimulating electrode array. In further embodiments, the anchored wire208 deployed within the deep cerebral vein can be used as both arecording electrode array and a stimulating electrode array.

FIG. 3A also illustrates that an electrode array 102 coupled to astent-electrode array 109 serving as the endovascular carrier 108 can beimplanted within an internal jugular vein superior to (or above) thejugular foramen of the subject. In some embodiments, the entirestent-electrode array 109 can be implanted in the internal jugular veinsuperior to the jugular foramen.

In other embodiments, at least part of the stent-electrode array 109 canbe implanted in the internal jugular vein superior to the jugularforamen. Implantation of the stent-electrode array 109 superior to thejugular foramen will be discussed in more detail in later sections.

In some embodiments, the stent-electrode array 109 implanted within theinternal jugular foramen can be used to stimulate an intracorporealtarget (e.g., a superior ganglion of the vagus nerve) of the subject. Inthis manner, the stent-electrode array 109 implanted within the internaljugular vein can be used as a stimulating electrode array.

FIG. 3A further illustrates that an electrode array 102 coupled to anendovascular carrier 108 (e.g., a coiled wire 200, a stent-electrodearray 109, or an anchored wire 208,) can be used as a recordingelectrode array to record an electrophysiological signal indicating aheart rate or change in heart rate (e.g., ictal tachycardia) of thesubject. This cardiac signal can be associated or correlated with theonset of epileptic seizures. For example, this electrophysiologicalsignal can be a cardiac arrhythmia known to be associated or correlatedwith a high likelihood of epileptic seizure onset.

As shown in FIG. 3A, the neuromodulation unit 104 can be implantedinferior to the head and neck of the subject. For example, as shown inFIG. 3A, the neuromodulation unit 104 can be implanted within a pectoralregion of the subject (e.g., beneath the pectoralis major muscle).

As previously discussed, in some embodiments, the pulse generator 110can be part of the neuromodulation unit 104. In other embodiments, thepulse generator 110 can be a standalone device separate from theneuromodulation unit 104. In these embodiments, the pulse generator 110can be implanted within a pectoral region of the subject (e.g., beneaththe pectoralis major muscle).

FIG. 3B illustrates that the neuromodulation unit 104 can be implantedwithin a forearm of the subject. In this embodiment, the neuromodulationsystem 100 can comprise an extracorporeal device 300 in the form of awearable device such as an armband 308. The implanted neuromodulationunit 104 can comprise a first magnetic component 118 (e.g., a receivingor secondary coil) and the armband 308 can comprise a second magneticcomponent 302 (e.g., a primary or transmission coil). The armband 308can charge or power the neuromodulation unit 104 via electromagneticinduction.

As previously discussed, in some embodiments, the pulse generator 110can be a standalone device separate from the neuromodulation unit 104.In these embodiments, the pulse generator 110 can be implanted withinthe forearm of the subject. The pulse generator 110 can comprise a firstmagnetic component 118 (e.g., a receiving or secondary coil) and anarmband 308, serving as the extracorporeal device 300, can comprise asecond magnetic component 302 (e.g., a primary or transmission coil).The armband 308 can charge or power the pulse generator 110 viaelectromagnetic induction.

FIG. 3A also illustrates that the extracorporeal device 300 can also beimplemented as a portable handheld device 304, a wand 306, or a wearabledevice (e.g., bracelet or watch). The extracorporeal device 300 can beused to recharge one or more batteries within the neuromodulation unit104, the pulse generator 110, or a combination thereof. In someembodiments, the extracorporeal device 300 can be used to activate thepulse generator 110 to transmit an electrical impulse to the stimulatingelectrode array.

FIGS. 4A-4C illustrate one embodiment of a transmission lead 106 used toconnect the electrode array 102 to the neuromodulation unit 104, thepulse generator 110, or a combination thereof. For example, thetransmission lead 106 can be used to connect the first electrode array102A or the second electrode array 102B to the neuromodulation unit 104,the pulse generator 110, or a combination thereof.

As shown in FIGS. 4A-4C, the transmission lead 106 can comprise at leastone variable length segment 400 in between the endovascular carrier 108and a transmission segment 402. A segment length 404 of the variablelength segment 400 can be adjusted (e.g., shortened or lengthened) afterthe transmission lead 106 is deployed within a bodily vessel (e.g.,vein, artery, or sinus) of the subject.

The transmission segment 402 can be a proximal segment of thetransmission lead 106 configured to connect or plug in to theneuromodulation unit 104 (e.g., into the header portion 114 of theneuromodulation unit 104). The transmission segment 402 can be made ofone or more conductive wires without shape memory. For example, thetransmission segment 402 can be made in part of platinum wire orplatinum-iridium wire. The transmission segment 402, along with othersegments of the transmission lead 106, can be covered by an insulator(e.g., polyurethane) or insulating coating.

FIGS. 4A-4C illustrate that the variable length segment 400 can beconnected or coupled to a proximal end of the endovascular carrier 108.For example, the endovascular carrier 108 can be a coiled wire 200 andthe variable length segment 400 can be connected or coupled directly tothe proximal end of the coiled wire 200.

The variable length segment 400 of the transmission lead 106 can be madein part of a shape-memory alloy. The variable length segment 400 of thetransmission lead 106 can also be made of a composite materialcomprising a shape-memory alloy. For example, the variable lengthsegment 400 of the transmission lead 106 can be made in part of Nitinol(e.g., Nitinol wire). In some embodiments, the variable length segment400 of the transmission lead 106 can be made of composite clad wire or aNitinol wire having a conductive (e.g., gold or platinum) wire core.

FIG. 4A illustrates the shape of the coiled wire 200 and thetransmission lead 106 when constricted within a delivery catheter orsheath. FIG. 4B illustrates the shape of the coiled wire 200 and thetransmission lead 106 when the coiled wire 200 and the transmission lead106 are deployed out of the delivery catheter or when the deliverycatheter or sheath is retracted.

As shown FIG. 4B, the variable length segment 400 of the transmissionlead 106 can be configured to automatically recover a preset orpretrained shape. In some embodiments, the preset or pretrained shapecan be a coiled configuration having loosely-wound coils or coils with alarger pitch or less turns than the coils of the coiled wire 200. Thevariable length segment 400 can automatically attain its loosely coiledconfiguration via shape memory when a delivery catheter or sheathcarrying the variable length segment 400 is retracted.

In certain embodiments, the preset or pretrained shape of the coilsformed by the variable length segment 400 can have a coil diameter lessor smaller than the diameter of the anticipated deployment orimplantation vessel. This ensures that the radial forces exerted by thecoils on the vessel lumen walls do not prevent the coils of the variablelength segment 400 from shifting, contracting, or expanding within thebodily vessel of the subject. In some instances, this contraction andexpansion can allow the segment length 404 of the variable lengthsegment 400 to vary (e.g., shorten or lengthen). For example, thevariable length segment 400 can lengthen by pulling on a proximal (ordistal) end of the variable length segment 400. The variable lengthsegment 400 can be shortened by pushing on a proximal end of thevariable length segment 400 when an endovascular carrier 108 coupled toa distal end of the variable length segment 400 is implanted orotherwise secured within a deployment vessel. The variable lengthsegment 400 can also be shortened by pushing on a distal end of thevariable length segment 400 when an endovascular carrier 108 coupled toa proximal end of the variable length segment 400 is implanted orotherwise secured within a deployment vessel.

In some embodiments, the variable length segment 400 can attain a coiledconfiguration when or only when a pushing force is applied to thevariable length segment 400 to compel or urge the variable lengthsegment 400 into the coiled configuration.

In further embodiments, the variable length segment 400 can have littleor no shape memory and the variable length segment 400 can be a segmentof the transmission lead 106 configured to curl up or deform when apushing force is applied to the variable length segment 400.

One technical problem faced by the applicants is how to design animplantable neuromodulation system comprising endovascular carriersconnected or coupled by transmission leads when the distance betweensuch endovascular carriers or the distance between such endovascularcarriers and an implantable neuromodulation unit or pulse generatordiffers by patient or treatment regimen. For example, differences inneck and torso lengths among subjects and where such endovascularcarriers are implanted within each subject requires a neuromodulationsystem that can adapt to different sized anatomy and differentimplantation requirements. One advantage of the neuromodulation system100 disclosed herein is the unique transmission leads 106 comprising thevariable length segment 400 disclosed herein that can allow theneuromodulation system 100 to be adapted to different sized patients andpatients with different implantation requirements.

In some embodiments, the transmission lead 106 can have a lead diameterof between 0.5 mm and 1.5 mm. More specifically, the transmission lead106 can have a lead diameter of between 0.5 mm and 1.0 mm.

In some embodiments, the transmission lead 106, or segments thereof, canbe covered by an insulator or insulating coating. For example, thetransmission lead 106, or segments thereof, can be covered bypolyurethane or a polyurethane coating.

In some embodiments, at least a segment of the transmission lead 106 canbe a cable comprising multiple conductive wires or transmission wirescoupled to the various electrodes 112 of the electrode array 102. Forexample, the transmission lead 106 can be a stranded cable comprising aplurality of conductive wires twisted and bundled together and coveredby an insulator or insulating material.

FIGS. 5A-5C illustrate an example method of implanting an embodiment ofan electrode array 102 (e.g., any of the first electrode array 102A orthe second electrode array 102B). The method can be used when anintracorporeal target 500 is close to but not adjacent to a vessel 502used to deliver or deploy the electrode array 102.

As shown in FIGS. 5A and 5B, when a delivery catheter 504 is moved intoposition near a vessel wall 506, an endovascular carrier 108 carryingthe electrode array 102 can be deployed out of the delivery catheter504. In the embodiment shown in FIGS. 5A-5C, the endovascular carrier108 can be an anchored wire 208 having the electrode array 102 coupledalong a segment of a biocompatible wire 202 or microwire (see, also,FIG. 2C).

The wire 202 or microwire can comprise a sharp distal end in the form ofa penetrating barb 508 or penetrating anchor coupled or detachablycoupled to the distal end of the wire 202 or microwire. The penetratingbarb 508 or penetrating anchor can allow the wire 202 or microwire topenetrate or create a puncture in the vessel wall 506 to allow the wire202 or microwire to extend through the vessel wall 506. The wire 202 ormicrowire can then direct the electrode array 102 closer to theintracorporeal target 500 (e.g., the target nerve or brain region) suchthat the electrode array 102 is positioned at or in close proximity tothe intracorporeal target 500.

FIG. 5C illustrates that once the delivery catheter 504 is retracted, awire segment 510 proximal to the electrode array 102 can automaticallytake the shape of a coil. The coil shape of the wire segment 510 can bepre-set prior to being introduced into the delivery catheter 504. Forexample, the wire segment 510 can have a lead diameter of about 1.0 mm(or less than 1.0 mm) and the vessel 502 can have a vessel diameter ofabout 6.0 mm. Once the delivery catheter 504 is removed, the wiresegment 510 can take the shape of a coil having a coil diameter ofgreater than 6.0 mm. The wire segment 510 can self-expand until the coilpushes against the internal vessel walls to secure the wire segment 510to the internal vessel walls. In this embodiment, the wire segment 510proximal to the electrode array 102 can be used to also secure theendovascular carrier 108. With the wire segment 510 and the electrodearray 102 in place, the penetrating barb 508 can be removed by a styletor other device extending through the delivery catheter 504.

FIG. 6 illustrates one embodiment of a method 600 of treating epilepsy.The method 600 can comprise detecting, using a first electrode array102A, an electrophysiological signal of a subject in step 602. In thismanner, the first electrode array 102A can act as a recording electrodearray. The first electrode array 102A can be affixed, secured, otherwisecoupled to the first endovascular carrier 108A (e.g., spaced out along alength of the first endovascular carrier 108A and/or coupled to aradially outer portion of the first endovascular carrier 108A). Thefirst endovascular carrier 108A can be implanted within an artery, vein,or sinus of the subject. Possible implantation sites for the firstendovascular carrier 108A will be discussed in more detail in thefollowing sections.

The method 600 can also comprise analyzing the electrophysiologicalsignal using a neuromodulation unit 104 implanted within the subject andelectrically coupled to the first electrode array 102A via one or moreconductive leads and/or a transmission lead 106 in step 604. Theneuromodulation unit 104 can be configured to analyze theelectrophysiological signal by (i) comparing the signal detected againstone or more thresholds (e.g., detecting a spike in the signal), (ii)detecting certain signal patterns or rhythmic activity in specificfrequency ranges, (iii) comparing absolute sample-to-sample amplitudedifferences within a predetermined time window, (iv) measuring a changein signal energy, or a combination thereof.

The method 600 can also comprise stimulating an intracorporeal target ofthe subject using a second electrode array 102B in response to theelectrophysiological signal detected in step 606. In this manner, thesecond electrode array 102B can act as a stimulating electrode array.The second electrode array 102B can be affixed, secured, or otherwisecoupled to the second endovascular carrier 108B (e.g., spaced out alonga length of the second endovascular carrier 108B and/or coupled to aradially outer portion of the second endovascular carrier 108B). Thesecond endovascular carrier 108B can be implanted within an artery,vein, or sinus of the subject superior to a base of the skull of thesubject.

FIG. 7 illustrates another embodiment of a method 700 of treatingepilepsy. The method 700 can comprise detecting, using a first electrodearray 102A, an electrophysiological signal of a subject in step 702. Inthis manner, the first electrode array 102A can act as a recordingelectrode array. The first electrode array 102A can be affixed, secured,otherwise coupled to an endovascular carrier 108 implantedendovascularly within an artery, vein, or sinus of the subject superiorto a base of the skull of the subject. For example, the endovascularcarrier 108 can be the endovascular carrier 214 depicted in FIG. 2D.

The first electrode array 102A can be spaced out along a length of theendovascular carrier 108 and/or coupled to a radially outer portion ofthe endovascular carrier 108. Possible implantation sites for theendovascular carrier 108 will be discussed in more detail in thefollowing sections.

The method 700 can also comprise analyzing the electrophysiologicalsignal using a neuromodulation unit 104 implanted within the subject andelectrically coupled to the first electrode array 102A via one or moreconductive leads and/or a transmission lead 106 in step 704. Theneuromodulation unit 104 can be configured to analyze theelectrophysiological signal by (i) comparing the signal detected againstone or more thresholds (e.g., detecting a spike in the signal), (ii)detecting certain signal patterns or rhythmic activity in specificfrequency ranges, (iii) comparing absolute sample-to-sample amplitudedifferences within a predetermined time window, (iv) measuring a changein signal energy, or a combination thereof.

The method 700 can also comprise stimulating an intracorporeal target ofthe subject using a second electrode array 102B in response to theelectrophysiological signal detected in step 706. The second electrodearray 102B can be spaced out along a length of the endovascular carrier108 and/or coupled to a radially outer portion of the endovascularcarrier 108. In this manner, the second electrode array 102B can act asa stimulating electrode array. The second electrode array 102B can beaffixed, secured, or otherwise coupled to the same endovascular carrier108 (e.g., spaced out along a length of the endovascular carrier 108and/or coupled to a radially outer portion of the endovascular carrier108). The electrodes of the second electrode array 102B can be separatefrom the electrodes of the first electrode array 102A.

Although FIGS. 6 and 7 disclose methods of treating epilepsy, it iscontemplated by this disclosure that the neuromodulation system 100disclosed herein can also be used in treating other disorders orconditions including headaches, bipolar disorder, obesity, Alzheimer’sdisease, Parkinson’s disease, rheumatoid arthritis, or inflammatorybowel disease. For example, a method of treating one of theaforementioned conditions/disorders can comprise detecting, using afirst electrode array 102A, an electrophysiological signal of a subjectassociated with or related to an onset of symptoms related to thecondition/disorder. The first electrode array 102A can be coupled to afirst endovascular carrier 108A implanted superior to a base of theskull of the subject. The method can also comprise analyzing theelectrophysiological signal using a neuromodulation unit 104 implantedwithin the subject and electrically coupled to the first electrode array102A. The method can further comprise stimulating an intracorporealtarget of the subject using a second electrode array 102B in response tothe electrophysiological signal detected. The second electrode array102B can be coupled to a second endovascular carrier 108B implantedendovascularly within the subject and electrically coupled to theneuromodulation unit 104. For example, stimulating the intracorporealtarget can comprise generating an electrical impulse using a pulsegenerator 110 of the neuromodulation unit 104. Stimulating theintracorporeal target can alleviate or lessen a symptom or contributingfactor of the condition/disorder.

FIG. 8A illustrates that the endovascular carrier 108 (including any ofthe first endovascular carrier 108A or the second endovascular carrier108B) can be implanted within the internal jugular vein 800 (e.g., theright internal jugular vein or the left internal jugular vein) superiorto a jugular foramen 802 of the subject. The jugular foramen 802 is acavity formed in the inferior portion of the base of the subject’sskull. The jugular foramen 802 is formed by the petrous part of thetemporal bone anteriorly and the occipital bone posteriorly.

When the endovascular carrier 108 is implanted within the internaljugular vein 800 superior to the jugular foramen 802, the electrodearray 102 coupled to the endovascular carrier 108 can be used tostimulate a vagus nerve 804 of the subject. In certain embodiments, theintracorporeal target or stimulation target can be the superior ganglion806 of the vagus nerve 804. In other embodiments, the intracorporealtarget or the stimulation target can be both the superior ganglion 806and the inferior ganglion 808 of the vagus nerve 804.

In some embodiments, a method of treating epilepsy can compriseimplanting a first electrode array 102A coupled to a first endovascularcarrier 108A in a cerebral or cortical vein or sinus of the subject torecord an electrophysiological signal of the subject associated orcorrelated with or indicative of the onset of an epileptic seizure. Themethod can also comprise implanting a second electrode array 102Bcoupled to a second endovascular carrier 108B (e.g., the stent-electrodearray 109) in the internal jugular vein 800 superior to the jugularforamen 802 to stimulate the vagus nerve 804 of the subject. Aneuromodulation unit 104 electrically coupled to the first electrodearray 102A and the second electrode array 102B can analyze theelectrophysiological signal and instruct a pulse generator 110 of theneuromodulation unit 104 to generate an electrical impulse to stimulatethe vagus nerve 804.

The electrical impulse can be biphasic, monophasic, sinusoidal, or acombination thereof. For example, the electrical impulse can becharge-balanced biphasic pulses. The pulse generator 110 can generatethe electrical impulse by increasing a current amplitude of theelectrical impulse from 0.25 mA to up to 2 mA in 0.1 mA steps andincreasing a voltage of the electrical impulse from 0 V to up to 10 V in0.25 V steps. The electrical impulse generated can have a pulse width ofbetween 250 µS to about 500 µS. A timing parameter of the electricalimpulse can also be adjusted to allow for different stimulation timingpatterns. The electrical impulse generated can have a frequency between10 Hz and 30 Hz.

In some embodiments, at least part of the endovascular carrier 108 canbe implanted within the internal jugular vein 800 superior to thejugular foramen 802. In additional embodiments, at least part of theendovascular carrier 108 can be implanted within a branch or tributaryof the internal jugular vein 800.

In additional embodiments, the endovascular carrier 108 can be implantedwithin the internal carotid artery 810 superior to the base of the skullof the subject. In further embodiments, the endovascular carrier 108 canbe implanted within the internal carotid artery 810 superior to acarotid foramen 812 of the subject. In other embodiments, at least partof the endovascular carrier 108 can be implanted within the internalcarotid artery 810 superior to the base of the skull of the subject. Infurther embodiments, at least part of the endovascular carrier 108 canbe implanted within the internal carotid artery 810 superior to thecarotid foramen 812. In these and other embodiments, the intracorporealtarget can be the vagus nerve 804 of the subject.

Although FIG. 8A illustrates the endovascular carrier 108 as astent-electrode array 109, it is contemplated by this disclosure thatany of the endovascular carriers 108 disclosed herein (including thecoiled wire 200 or the anchored wire 208) can be implanted within theinternal jugular vein 800. Moreover, any of the endovascular carriers108 disclosed herein (including any of the stent-electrode array 109,the coiled wire 200, or the anchored wire 208) can be implanted withinthe internal carotid artery 810.

FIGS. 8B and 8C illustrate a proximity of the vagus nerve 804 to theinternal jugular vein 800. In most subjects, at least part of the vagusnerve 804 extending through the neck and into the skull of the subjectis in contact with the internal jugular vein 800 or adjacent to theinternal jugular vein 800 (i.e., separated from the internal jugularvein 800 by less than 2.0 mm).

For example, FIG. 8B illustrates a partial sectional view of atransverse section of a subject at the level of the C6 vertebra showingthe vagus nerve 804 and surrounding vessels, including the internaljugular vein 800. As previously discussed, the internal jugular vein 800can serve as a possible implantation site for an endovascular carrier108 carrying an electrode array 102 (e.g., a stimulating electrodearray).

In some embodiments not shown in the figures, the endovascular carrier108 can also be implanted within a common carotid artery (outside of theskull of the subject) or an external carotid artery.

One technical problem faced by the applicants is that endovascularcarriers 108 implanted in vessels within the neck of the subject canwear down over time as a result of the natural motion of the neck (e.g.,bending, flexion, extension, rotation, etc.). Moreover, endovascularcarriers 108 implanted in vessels within the neck can also be damaged byexternal forces applied to the neck of the subject. One advantage ofimplanting the endovascular carriers 108 within the skull of the subject(e.g., in an internal carotid artery superior to a jugular foramen) isthat the skull acts as a protective casing for the endovascular carrier108 and only one or more thin transmission leads 106 extend through theneck of the subject. This can also increase patient comfort and increasethe deployed lifespan of the endovascular carrier. Moreover,electrophysiological recordings taken from electrodes within the skullare less impacted by extraneous signals such as heart beating artifacts.

FIGS. 9A-9G illustrate certain veins and sinuses of the subject that canserve as implantation sites for the endovascular carriers 108 carryingthe electrode arrays 102. Moreover, FIGS. 9A-9G also illustrate certainintracorporeal targets or stimulation targets that can be stimulated aspart of a treatment for epilepsy or other disorders/conditions.

In some embodiments, the first endovascular carrier 108A carrying thefirst electrode array 102A can be implanted within a venous sinus of thesubject. For example, the first endovascular carrier 108A carrying thefirst electrode array 102A can be implanted within a superior sagittalsinus 900, an inferior sagittal sinus 902, a sigmoid sinus 904, atransverse sinus 906, or a straight sinus 908.

In other embodiments, the first endovascular carrier 108A carrying thefirst electrode array 102A can be implanted within a superficialcerebral vein of the subject. For example, the first endovascularcarrier 108A carrying the first electrode array 102A can be implantedwithin at least one of a vein of Labbe 910, a vein of Trolard 912, aSylvian vein 914, and a Rolandic vein 916.

The first endovascular carrier 108A carrying the first electrode array102A can also be implanted within a deep cerebral vein of the subject.For example, the first endovascular carrier 108A carrying the firstelectrode array 102A can be implanted within at least one of a vein ofRosenthal 918, a vein of Galen 920, a superior thalamostriate vein 922,an inferior thalamostriate vein 924, and an internal cerebral vein 926.

In further embodiments, the first endovascular carrier 108A carrying thefirst electrode array 102A can also be implanted within at least one ofa central sulcal vein, a post-central sulcal vein, and a pre-centralsulcal vein. In additional embodiments, the first endovascular carrier108A can also be implanted or configured to be implanted within a vesselextending through a hippocampus or amygdala of the subject.

Once implanted, the first electrode array 102A can be configured todetect or record an electrophysiological signal of the subjectassociated or correlated with the onset of epileptic seizures. In someembodiments, the electrophysiological signal can be a local fieldpotential (LFP) and/or an intracranial/cortical EEG measured within acerebral or cortical vessel (e.g., a venous sinus or cortical vein). Inother embodiments, the electrophysiological signal can be anelectrocorticography (ECoG) signal.

As previously discussed, the neuromodulation unit 104 can furthercomprise a telemetry unit 120 or telemetry module (e.g., a telemetryhardware module, a telemetry software module, or a combination thereof).The telemetry unit 120 can be configured to analyze theelectrophysiological signal detected or recorded by the first electrodearray 102A. For example, the one or more processors of theneuromodulation unit 104 (or the telemetry unit 120 within theneuromodulation unit 104) can be programmed to execute instructionsstored in the one or more memory units to analyze theelectrophysiological signal by: (i) comparing the signal detectedagainst one or more thresholds (e.g., detecting a spike in the signal),(ii) detecting certain signal patterns or rhythmic activity in specificfrequency ranges, (iii) comparing absolute sample-to-sample amplitudedifferences within a predetermined time window, (iv) measuring a changein signal energy, or a combination thereof. The neuromodulation unit 104can then instruct a pulse generator 110 (e.g., a pulse generatorprovided as part of the neuromodulation unit 104 or a pulse generatorseparate from the neuromodulation unit 104) to generate an electricalimpulse to stimulate an intracorporeal target or stimulation target viathe second electrode array 102B coupled to a second endovascular carrier108B.

As previously discussed, when the intracorporeal target is a vagus nerveof the subject, the second endovascular carrier 108B can be implantedwithin an internal jugular vein (either a right internal jugular vein ora left internal jugular vein) or an internal carotid artery.

In other embodiments, the intracorporeal target or stimulation targetcan be the cerebellum 928 of the subject. In these embodiments, thesecond endovascular carrier 108B carrying the second electrode array102B can be implanted within at least one of a sigmoid sinus 904 and astraight sinus 908 of the subject. Moreover, the second endovascularcarrier 108B carrying the second electrode array 102B can also beimplanted within a transverse sinus 906 of the subject. At least part ofthe cerebellum 928 is adjacent to the sigmoid sinus 904, the straightsinus 908, and the transverse sinus 906 (i.e., separated by less than2.0 mm).

In additional embodiments, the intracorporeal target or stimulationtarget can be the motor cortex 930 of the subject. In these embodiments,the second endovascular carrier 108B carrying the second electrode array102B can be implanted within at least one of an inferior sagittal sinus902, a central sulcal vein, a post-central sulcal vein, and apre-central sulcal vein of the subject. Moreover, the secondendovascular carrier 108B carrying the second electrode array 102B canalso be implanted within a superior sagittal sinus 900 of the subject.At least part of the motor cortex 930 is adjacent to the superiorsagittal sinus 900, the central sulcal vein, the post-central sulcalvein, and the pre-central sulcal vein (i.e., separated by less than 2.0mm).

Moreover, at least part of the motor cortex 930 is between about 5.0 mmto about 10.0 mm from the inferior sagittal sinus 902. When the secondendovascular carrier 108B carrying the second electrode array 102B isimplanted within the inferior sagittal sinus 902, the intracorporealtarget stimulated can also include a fornix 944 of the subject. Thefornix 944 can be between about 10.0 mm to about 15.0 mm from theinferior sagittal sinus 902.

In further embodiments, the second endovascular carrier 108B carryingthe second electrode array 102B can be implanted within a superficialcerebral vein. For example, the second endovascular carrier 108Bcarrying the second electrode array 102B can be implanted within atleast one of a vein of Labbe 910, a vein of Trolard 912, a Sylvian vein914, and a Rolandic vein 916.

In some embodiments, the second endovascular carrier 108B carrying thesecond electrode array 102B can be implanted within a deep cerebralvein. For example, the second endovascular carrier 108B carrying thesecond electrode array 102B can be implanted within at least one of avein of Rosenthal 918, a vein of Galen 920, a superior thalamostriatevein 922, and an internal cerebral vein 926.

When the second endovascular carrier 108B carrying the second electrodearray 102B is implanted within the vein of Rosenthal 918, theintracorporeal target stimulated can include at least one of thecerebellum 928, the anterior nucleus of thalamus 932, the centromediannucleus of thalamus 934, the hippocampus 936, the subthalamic nucleus938, and the caudal zone incerta 940. The vein of Rosenthal 918 can bebetween about 10.0 mm to about 15.0 mm from at least part of thecerebellum 928, the anterior nucleus of thalamus 932, and thecentromedian nucleus of thalamus 934. The vein of Rosenthal 918 can bebetween about 5.0 mm to about 10.0 mm from at least part of thehippocampus 936, the subthalamic nucleus 938, and the caudal zoneincerta 940.

When the second endovascular carrier 108B carrying the second electrodearray 102B is implanted within the internal cerebral vein 926, theintracorporeal target stimulated can include at least one of theanterior nucleus of thalamus 932, the centromedian nucleus of thalamus934, the hypothalamus 942, the fornix 944, and the caudal zone incerta940. The internal cerebral vein 926 can be between about 10.0 mm toabout 15.0 mm from at least part of the hypothalamus 942 and the caudalzone incerta 940. The internal cerebral vein 926 can be between about5.0 mm to about 10.0 mm from at least part of the anterior nucleus ofthalamus 932. The internal cerebral vein 926 can be between about 2.0 mmto about 5.0 mm from at least part of the fornix 944. The internalcerebral vein 926 can be adjacent to (i.e., separated by less than 2.0mm from) the centromedian nucleus of thalamus 934.

When the second endovascular carrier 108B carrying the second electrodearray 102B is implanted within the superior thalamostriate vein 922, theintracorporeal target stimulated can include at least one of theanterior nucleus of thalamus 932, the centromedian nucleus of thalamus934, and the fornix 944. The superior thalamostriate vein 922 can beadjacent to (i.e., separated by less than 2.0 mm from) the anteriornucleus of thalamus 932, the centromedian nucleus of thalamus 934, andthe fornix 944.

In certain embodiments, the second endovascular carrier 108B carryingthe second electrode array 102B can also be implanted or configured tobe implanted within a vessel extending through a hippocampus or amygdalaof the subject.

In some embodiments, stimulating the intracorporeal target or thestimulation target via the second electrode array 102B can increaseblood flow to the intracorporeal target or raise levels of certainneurotransmitters involved in suppressing seizure activity. Moreover,stimulating the intracorporeal target via the second electrode array102B can also lead to sodium-channel inactivation (using high-frequencystimulation), long-term depression of certain neurotransmitters (usinghigh-frequency stimulation), and/or glutamatergic depression (using bothlow-frequency and high-frequency stimulation).

For example, when stimulating cortical or cerebral targets, theelectrical impulse can be bipolar with the voltage of the electricalimpulse increased from 1V to 7 V in 0.25 V steps. The electrical impulsegenerated can have a pulse width of between 90 µS to about 540 µS, afrequency between about 3 Hz to 5 Hz in a low-frequency range, and afrequency between about 50 Hz to 130 Hz in a high-frequency range.

Although recording and stimulating using electrode arrays 102 coupled todifferent endovascular carriers 108 are discussed, it is contemplated bythis disclosure that the same endovascular carrier (see, e.g., theendovascular carrier 214 shown in 2D) can carry both the first electrodearray 102A and the second electrode array 102B. For example, anexpandable stent or scaffold can carry both recording electrode arraysand stimulating electrode arrays on the same expandable stent orscaffold.

FIG. 10 illustrates one embodiment of a method of deploying ordelivering the endovascular carriers 108 (e.g., the first endovascularcarrier 108A and the second endovascular carrier 108B) to theirrespective implantation sites. Although the figures illustrate twoendovascular carriers 108 being deployed, it is contemplated by thisdisclosure that similar apparatus or similar methods can also be used todeliver a singular endovascular carrier (see, e.g., endovascular carrier214 of FIG. 2D) carrying separate electrode arrays 102 or three or moreendovascular carriers.

As shown in FIG. 10 , a first delivery catheter 1000 can be deployedthrough a jugular incision to the superior sagittal sinus 900. The firstdelivery catheter 1000 can be deployed under angiographic guidance.Although the superior sagittal sinus 900 is shown in the figures, itshould be understood by one of ordinary skill in the art that thecatheter and carriers can be deployed into any vein, sinus, or artery ofthe subject.

A first endovascular carrier 108A carrying a first electrode array 102A(not shown in FIG. 10 , see FIG. 1 ) can be deployed or otherwisedelivered through the first delivery catheter 1000. For example, thefirst endovascular carrier 108A can be a stent-electrode array 109configured to self expand into position within the superior sagittalsinus 900.

In some embodiments, the first electrode array 102A coupled to the firstendovascular carrier 108A can be used as a recording electrode array. Inother embodiments, the first electrode array 102A can be used as astimulating electrode array or both a recording electrode array and astimulating electrode array. Once the first endovascular carrier 108A ispositioned in place, the first delivery catheter 1000 can be removedfrom the vasculature of the subject.

FIG. 10 also illustrates that a second delivery catheter 1002 can bedeployed through the same jugular incision to the internal cerebral vein926 overlying the anterior nucleus of thalamus 932. The second deliverycatheter 1002 can be deployed under angiographic guidance.

A second endovascular carrier 108B carrying a second electrode array102B (not shown in FIG. 10 , see FIG. 1 ) can be deployed or otherwisedelivered through the second delivery catheter 1002. For example, thesecond endovascular carrier 108B can be a stent-electrode array 109configured to self expand into position within the internal cerebralvein 926.

In some embodiments, the second electrode array 102B coupled to thesecond endovascular carrier 108B can be used as a stimulating electrodearray. In other embodiments, the second electrode array 102B can be usedas a recording electrode array or both a stimulating electrode array anda recording electrode array. Once the second endovascular carrier 108Bis positioned in place, the second delivery catheter 1002 can be removedfrom the vasculature of the subject.

Moreover, as shown in FIG. 10 , a first transmission lead 106A coupledto the first electrode array 102A on the first endovascular carrier 108Acan extend through the neck of the subject (e.g., through a jugularvein) and a proximal end of the first transmission lead 106A can beinserted into a neuromodulation unit 104 (e.g., into a header portion114, see, FIG. 1 ) implanted within the subject. In addition, a secondtransmission lead 106B coupled to the second electrode array 102B on thesecond endovascular carrier 108B can extend through the neck of thesubject and a proximal end of the second transmission lead 106B can beinserted into the neuromodulation unit 104.

FIG. 11 illustrates another embodiment of a method of deploying ordelivering the endovascular carriers 108 (e.g., the first endovascularcarrier 108A and the second endovascular carrier 108B) to theirrespective implantation sites. Although the figures illustrate twoendovascular carriers 108 being deployed, it is contemplated by thisdisclosure that similar apparatus or similar methods can also be used todeliver a singular endovascular carrier (see, e.g., endovascular carrier214 of FIG. 2D) carrying separate electrode arrays 102 or three or moreendovascular carriers.

As shown in FIG. 11 , a first delivery catheter 1100 can be deployedthrough a jugular incision to the superior sagittal sinus 900. The firstdelivery catheter 1100 can be deployed under angiographic guidance.Although the superior sagittal sinus 900 is shown in the figures, itshould be understood by one of ordinary skill in the art that thecatheter and carriers can be deployed into any vein, sinus, or artery ofthe subject.

A first endovascular carrier 108A carrying a first electrode array 102A(not shown in FIG. 11 , see FIG. 1 ) can be deployed or otherwisedelivered through the first delivery catheter 1100. For example, thefirst endovascular carrier 108A can be a stent-electrode array 109configured to self expand into position within the superior sagittalsinus 900.

In some embodiments, the first electrode array 102A coupled to the firstendovascular carrier 108A can be used as a recording electrode array. Inother embodiments, the first electrode array 102A can be used as astimulating electrode array or both a recording electrode array and astimulating electrode array. Once the first endovascular carrier 108A ispositioned in place, the first delivery catheter 1000 can be removedfrom the vasculature of the subject.

FIG. 11 also illustrates that the first delivery catheter 1100 can beretracted proximally and a second delivery catheter 1102 can be deployedthrough the retracted first delivery catheter 1100. The second deliverycatheter 1002 can be deployed to the internal cerebral vein 926overlying the anterior nucleus of thalamus 932. The second deliverycatheter 1002 can be deployed under angiographic guidance.

A second endovascular carrier 108B carrying a second electrode array102B (not shown in FIG. 11 , see FIG. 1 ) can be deployed or otherwisedelivered through the second delivery catheter 1002. For example, thesecond endovascular carrier 108B can be a stent-electrode array 109configured to self expand into position within the internal cerebralvein 926.

In some embodiments, the second electrode array 102B coupled to thesecond endovascular carrier 108B can be used as a stimulating electrodearray. In other embodiments, the second electrode array 102B can be usedas a recording electrode array or both a stimulating electrode array anda recording electrode array. Once the second endovascular carrier 108Bis positioned in place, the second delivery catheter 1102 can be removedfrom the vasculature of the subject.

A first transmission lead 106A coupled to the first electrode array 102Aon the first endovascular carrier 108A can extend through the neck ofthe subject (e.g., through a jugular vein) and a proximal end of thefirst transmission lead 106A can be inserted into a neuromodulation unit104 (e.g., into a header portion 114, see, FIG. 1 ) implanted within thesubject. In addition, a second transmission lead 106B coupled to thesecond electrode array 102B on the second endovascular carrier 108B canextend through the neck of the subject and a proximal end of the secondtransmission lead 106B can be inserted into the neuromodulation unit104.

FIG. 12 illustrates another embodiment of a method of deploying ordelivering the endovascular carriers 108 (e.g., the first endovascularcarrier 108A and the second endovascular carrier 108B) to theirrespective implantation sites. Although the figures illustrate twoendovascular carriers 108 being deployed, it is contemplated by thisdisclosure that similar apparatus or similar methods can also be used todeliver three or more endovascular carriers.

As shown in FIG. 12 , a delivery catheter 1200 can be deployed through ajugular incision to the superior sagittal sinus 900 and then continuingon to the internal cerebral vein 926 overlying the anterior nucleus ofthalamus 932. The delivery catheter 1200 can be deployed underangiographic guidance.

Although the superior sagittal sinus 900 is shown in the figures, itshould be understood by one of ordinary skill in the art that thecatheter and carriers can be deployed into any vein, sinus, or artery ofthe subject.

The second endovascular carrier 108B carrying the second electrode array102B (not shown in FIG. 12 , see FIG. 1 ) can be deployed or otherwisedelivered through the delivery catheter 1200. For example, the secondendovascular carrier 108B can be a stent-electrode array 109 configuredto self expand into position within the internal cerebral vein 926.

In some embodiments, the second electrode array 102B coupled to thesecond endovascular carrier 108B can be used as a recording electrodearray. In other embodiments, the second electrode array 102B can be usedas a stimulating electrode array or both a recording electrode array anda stimulating electrode array. Once the second endovascular carrier 108Bis positioned in place, the delivery catheter 1200 can be retracteduntil the distal end of the delivery catheter 1200 is in place to deploythe first endovascular carrier 108A into the superior sagittal sinus 900of the subject. The first endovascular carrier 108A can carry the firstelectrode array 102A (not shown in FIG. 12 , see FIG. 1 ). The firstendovascular carrier 108A can be a stent-electrode array 109 configuredto self expand into position within the superior sagittal sinus 900.

In some embodiments, the first electrode array 102A coupled to the firstendovascular carrier 108A can be used as a stimulating electrode array.In other embodiments, the first electrode array 102A can be used as arecording electrode array or both a stimulating electrode array and arecording electrode array. Once the first endovascular carrier 108A ispositioned in place, the delivery catheter 1200 can be removed from thevasculature of the subject.

Retracting the delivery catheter 1200 can expose a singular transmissionlead 106 connecting the first endovascular carrier 108A to the secondendovascular carrier 108B. The singular transmission lead 106 can extendthrough the neck of the subject (e.g., through a jugular vein) and aproximal end of the transmission lead 106 can be inserted into aneuromodulation unit 104 (e.g., into a header portion 114, see, FIG. 1 )implanted within the subject.

FIG. 13 illustrates an embodiment of a delivery catheter 1300 comprisinga first endovascular carrier 108A and a second endovascular carrier 108Bconnected by a bifurcated transmission lead 1302. As shown in FIG. 13 ,a first branch 1304 of the bifurcated transmission lead 1302 can beconnected or coupled to the first endovascular carrier 108A and a secondbranch 1306 of the bifurcated transmission lead 1302 can be connected orcoupled to the second endovascular carrier 108B. At least one guidewire1308 can extend alongside at least one of the branches of the bifurcatedtransmission lead 1302. The guidewire 1308 can extend through a lumen ofone of the endovascular carriers 108 (e.g., the second endovascularcarrier 108B) and be detachably coupled to a tip 1310 of theendovascular carrier 108.

Another method of deploying or delivering the endovascular carriers 108(e.g., the first endovascular carrier 108A and the second endovascularcarrier 108B) to their respective implantation sites can comprisedeploying the delivery catheter 1300 through a jugular incision to thesuperior sagittal sinus 900. The delivery catheter 1300 can be deployedunder angiographic guidance.

A first endovascular carrier 108A carrying a first electrode array 102A(not shown in FIG. 13 , see FIG. 1 ) can be deployed or otherwisedelivered through the delivery catheter 1300. For example, the firstendovascular carrier 108A can be a stent-electrode array 109 configuredto self expand into position within the superior sagittal sinus 900.

In some embodiments, the first electrode array 102A coupled to the firstendovascular carrier 108A can be used as a recording electrode array. Inother embodiments, the first electrode array 102A can be used as astimulating electrode array or both a recording electrode array and astimulating electrode array. Once the first endovascular carrier 108A ispositioned in place, the delivery catheter 1300 can be retractedproximally and a second endovascular carrier 108B carrying a secondelectrode array 102B (not shown in FIG. 13 , see FIG. 1 ) can bedeployed through the retracted delivery catheter 1300 into a secondimplantation site (e.g., the internal cerebral vein 926 overlying theanterior nucleus of thalamus 932 of the subject). The guidewire 1308 canbe used to guide the second endovascular carrier 108 into place withinthe second implantation site.

For example, the second endovascular carrier 108B can be astent-electrode array 109 configured to self expand into position withina deployed vessel such as the internal cerebral vein 926. In someembodiments, the second electrode array 102B coupled to the secondendovascular carrier 108B can be used as a stimulating electrode array.In other embodiments, the second electrode array 102B can be used as arecording electrode array or both a stimulating electrode array and arecording electrode array. Once the second endovascular carrier 108B ispositioned in place, the delivery catheter 1300 and the guidewire 1308can be removed from the vasculature of the subject.

Retracting the delivery catheter 1300 can expose the bifurcatedtransmission lead 1302 connecting the first endovascular carrier 108A tothe second endovascular carrier 108B. The transmission lead 1302 canextend through the neck of the subject (e.g., through a jugular vein)and a proximal end of the transmission lead 1302 can be inserted into aneuromodulation unit 104 (e.g., into a header portion 114, see, FIG. 1 )implanted within the subject.

One technical advantage of the closed-loop neuromodulation system 100disclosed herein is that the system 100 can be delivered through aminimally invasive procedure, via angiography, to a vessel near anintracorporeal/stimulation target (e.g., the vagus nerve) withoutphysically contacting or potentially causing damage to theintracorporeal/stimulation target (e.g., causing damage to the vagusnerve).

Another technical advantage of the neuromodulation system 100 disclosedherein is that when the first endovascular carrier 108A (carrying thefirst electrode array 102A or the recording electrode array) isimplanted within a cortical/cerebral vein or sinus and the secondendovascular carrier 108B (carrying the second electrode array 10B orthe stimulating electrode array) is implanted within a cortical/cerebralvein or sinus or within a vein or artery superior to the skull of thesubject, the skull of the subject can act as a protective casing thatprotects the carriers from potentially destructive external forces andimproves the electrophysiological signals detected or recorded.

Yet another technical advantage of the neuromodulation system 100disclosed herein is that the system 100 can provide a closed-loop orresponsive stimulation whereby an electrophysiological signal from thesubject is detected or otherwise acquired and used as the impetus totrigger the electrical stimulation. An added advantage of the systemoperating in a closed-loop or responsive mode is that the battery lifeof the various electronic components of the system can be extended suchthat such electronic components are only activated when a seizure isimminent or when the subject is observed to be in a high seizure riskstate.

A number of embodiments have been described. Nevertheless, it will beunderstood by one of ordinary skill in the art that various changes andmodifications can be made to this disclosure without departing from thespirit and scope of the embodiments. Elements of systems, devices,apparatus, and methods shown with any embodiment are exemplary for thespecific embodiment and can be used in combination or otherwise on otherembodiments within this disclosure. For example, the steps of anymethods depicted in the figures or described in this disclosure do notrequire the particular order or sequential order shown or described toachieve the desired results. In addition, other steps operations may beprovided, or steps or operations may be eliminated or omitted from thedescribed methods or processes to achieve the desired results. Moreover,any components or parts of any apparatus or systems described in thisdisclosure or depicted in the figures may be removed, eliminated, oromitted to achieve the desired results. In addition, certain componentsor parts of the systems, devices, or apparatus shown or described hereinhave been omitted for the sake of succinctness and clarity.

Accordingly, other embodiments are within the scope of the followingclaims and the specification and/or drawings may be regarded in anillustrative rather than a restrictive sense.

Each of the individual variations or embodiments described andillustrated herein has discrete components and features which may bereadily separated from or combined with the features of any of the othervariations or embodiments. Modifications may be made to adapt aparticular situation, material, composition of matter, process, processact(s) or step(s) to the objective(s), spirit or scope of the presentinvention.

Methods recited herein may be carried out in any order of the recitedevents that is logically possible, as well as the recited order ofevents. Moreover, additional steps or operations may be provided orsteps or operations may be eliminated to achieve the desired result.

Furthermore, where a range of values is provided, every interveningvalue between the upper and lower limit of that range and any otherstated or intervening value in that stated range is encompassed withinthe invention. Also, any optional feature of the inventive variationsdescribed may be set forth and claimed independently, or in combinationwith any one or more of the features described herein. For example, adescription of a range from 1 to 5 should be considered to havedisclosed subranges such as from 1 to 3, from 1 to 4, from 2 to 4, from2 to 5, from 3 to 5, etc. as well as individual numbers within thatrange, for example 1.5, 2.5, etc. and any whole or partial incrementstherebetween.

All existing subject matter mentioned herein (e.g., publications,patents, patent applications) is incorporated by reference herein in itsentirety except insofar as the subject matter may conflict with that ofthe present invention (in which case what is present herein shallprevail). The referenced items are provided solely for their disclosureprior to the filing date of the present application. Nothing herein isto be construed as an admission that the present invention is notentitled to antedate such material by virtue of prior invention.

Reference to a singular item, includes the possibility that there areplural of the same items present. More specifically, as used herein andin the appended claims, the singular forms “a,” “an,” “said” and “the”include plural referents unless the context clearly dictates otherwise.It is further noted that the claims may be drafted to exclude anyoptional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely,”“only” and the like in connection with the recitation of claim elements,or use of a “negative” limitation. Unless defined otherwise, alltechnical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

Reference to the phrase “at least one of”, when such phrase modifies aplurality of items or components (or an enumerated list of items orcomponents) means any combination of one or more of those items orcomponents. For example, the phrase “at least one of A, B, and C” means:(i) A; (ii) B; (iii) C; (iv) A, B, and C; (v) A and B; (vi) B and C; or(vii) A and C.

In understanding the scope of the present disclosure, the term“comprising” and its derivatives, as used herein, are intended to beopen-ended terms that specify the presence of the stated features,elements, components, groups, integers, and/or steps, but do not excludethe presence of other unstated features, elements, components, groups,integers and/or steps. The foregoing also applies to words havingsimilar meanings such as the terms, “including”, “having” and theirderivatives. Also, the terms “part,” “section,” “portion,” “member”“element,” or “component” when used in the singular can have the dualmeaning of a single part or a plurality of parts. As used herein, thefollowing directional terms “forward, rearward, above, downward,vertical, horizontal, below, transverse, laterally, and vertically” aswell as any other similar directional terms refer to those positions ofa device or piece of equipment or those directions of the device orpiece of equipment being translated or moved.

Finally, terms of degree such as “substantially”, “about” and“approximately” as used herein mean the specified value or the specifiedvalue and a reasonable amount of deviation from the specified value(e.g., a deviation of up to ±0.1%, ±1%, ±5%, or ±10%, as such variationsare appropriate) such that the end result is not significantly ormaterially changed. For example, “about 1.0 cm” can be interpreted tomean “1.0 cm” or between “0.9 cm and 1.1 cm.” When terms of degree suchas “about” or “approximately” are used to refer to numbers or valuesthat are part of a range, the term can be used to modify both theminimum and maximum numbers or values.

This disclosure is not intended to be limited to the scope of theparticular forms set forth, but is intended to cover alternatives,modifications, and equivalents of the variations or embodimentsdescribed herein. Further, the scope of the disclosure fully encompassesother variations or embodiments that may become obvious to those skilledin the art in view of this disclosure.

We claim:
 1. A method of treating epilepsy, comprising: detecting, usinga first electrode array, an electrophysiological signal of a subject,wherein the first electrode array is coupled to a first endovascularcarrier implanted within the subject; analyzing the electrophysiologicalsignal using a neuromodulation unit implanted within the subject andelectrically coupled to the first electrode array; and stimulating anintracorporeal target of the subject using a second electrode array inresponse to the electrophysiological signal detected, wherein the secondelectrode array is electrically coupled to the neuromodulation unit, andwherein the second electrode array is coupled to a second endovascularcarrier implanted within a superficial cerebral vein of the subject. 2.The method of claim 1, wherein the superficial cerebral vein is at leastone of a vein of Labbe, a vein of Trolard, a Sylvian vein, and aRolandic vein.
 3. The method of claim 1, wherein the first endovascularcarrier is implanted within at least one of a superior sagittal sinus,an inferior sagittal sinus, a sigmoid sinus, a transverse sinus, and astraight sinus of the subject.
 4. The method of claim 1, wherein thefirst endovascular carrier is implanted within at least one of a vein ofLabbe, a vein of Trolard, a Sylvian vein, and a Rolandic vein of thesubject.
 5. The method of claim 1, wherein the first endovascularcarrier is implanted within at least one of a vein of Rosenthal, a veinof Galen, a superior thalamostriate vein, and an internal cerebral veinof the subject.
 6. The method of claim 1, wherein the first endovascularcarrier is implanted within at least one of a central sulcal vein, apost-central sulcal vein, and a pre-central sulcal vein of the subject.7. The method of claim 1, wherein the neuromodulation unit is implantedwithin a forearm of the subject.
 8. The method of claim 7, whereinstimulating the intracorporeal target further comprises generating anelectrical impulse using a pulse generator of the neuromodulation unit,and wherein the pulse generator is powered and activated by anextracorporeal device, and wherein the extracorporeal device is providedas part of an armband.
 9. The method of claim 1, wherein at least one ofthe first endovascular carrier and the second endovascular carrier is anexpandable stent or endovascular scaffold comprising an electrode arraycoupled to the expandable stent or endovascular scaffold.
 10. The methodof claim 1, wherein stimulating the intracorporeal target furthercomprises generating an electrical impulse using a pulse generator ofthe neuromodulation unit, and wherein the pulse generator is configuredto generate the electrical impulse by increasing a current amplitude ofthe electrical impulse from 0 mA to up to 10 mA in 0.1 mA steps andincreasing a voltage of the electrical impulse from 0 V to up to 10 V in0.25 V steps, wherein a pulse width of the electrical impulse generatedis configured to be between 25 µS to about 600 µS, and wherein afrequency of the electrical impulse generated is configured to bebetween 1 Hz and 400 Hz.
 11. A method of treating epilepsy, comprising:detecting, using a first electrode array, an electrophysiological signalof a subject, wherein the first electrode array is coupled to a firstendovascular carrier implanted within the subject; analyzing theelectrophysiological signal using a neuromodulation unit implantedwithin the subject and electrically coupled to the first electrodearray; and stimulating an intracorporeal target of the subject using asecond electrode array in response to the electrophysiological signaldetected, wherein the second electrode array is electrically coupled tothe neuromodulation unit, and wherein the second electrode array iscoupled to a second endovascular carrier implanted within a deepcerebral vein of the subject.
 12. The method of claim 11, wherein thedeep cerebral vein is at least one of a vein of Rosenthal, a vein ofGalen, a superior thalamostriate vein, and an internal cerebral vein.13. The method of claim 11, wherein the first endovascular carrier isimplanted within at least one of a superior sagittal sinus, an inferiorsagittal sinus, a sigmoid sinus, a transverse sinus, and a straightsinus of the subject.
 14. The method of claim 11, wherein the firstendovascular carrier is implanted within at least one of a vein ofLabbe, a vein of Trolard, a Sylvian vein, and a Rolandic vein of thesubject.
 15. The method of claim 11, wherein the first endovascularcarrier is implanted within at least one of a vein of Rosenthal, a veinof Galen, a superior thalamostriate vein, and an internal cerebral veinof the subject.
 16. The method of claim 11, wherein the firstendovascular carrier is implanted within at least one of a centralsulcal vein, a post-central sulcal vein, and a pre-central sulcal veinof the subject.
 17. A method of treating epilepsy, comprising:detecting, using a first electrode array, an electrophysiological signalof a subject, wherein the first electrode array is coupled to a firstendovascular carrier implanted within the subject; analyzing theelectrophysiological signal using a neuromodulation unit implantedwithin the subject and electrically coupled to the first electrodearray; and stimulating an intracorporeal target of the subject using asecond electrode array in response to the electrophysiological signaldetected, wherein the second electrode array is electrically coupled tothe neuromodulation unit, and wherein the second electrode array iscoupled to a second endovascular carrier implanted within at least oneof a central sulcal vein, a post-central sulcal vein, and a pre-centralsulcal vein of the subject.
 18. The method of claim 1, wherein the firstendovascular carrier is implanted within at least one of a superiorsagittal sinus, an inferior sagittal sinus, a sigmoid sinus, atransverse sinus, and a straight sinus of the subject.
 19. The method ofclaim 1, wherein the first endovascular carrier is implanted within atleast one of a vein of Labbe, a vein of Trolard, a Sylvian vein, and aRolandic vein of the subject.
 20. The method of claim 1, wherein thefirst endovascular carrier is implanted within at least one of a vein ofRosenthal, a vein of Galen, a superior thalamostriate vein, and aninternal cerebral vein of the subject.